properties (Wise et al., 1976; Carr and White, 1986; Mayer and Parker, 1993). ...... adolescence (DiFranza et al., 2002; O'Loughlin et al., 2003; Gervais et ...... Cutler G. B., Jr., Glenn M., Bush M., Hodgen G. D., Graham C. E., Loriaux D. L. (1978).
AGE DIFFERENCES IN THE VULNERABILITY TO NICOTINE ADDICTION: EVIDENCE FROM A RAT MODEL OF ADOLESCENT NICOTINE TAKING
by
Megan Joyce Shram
A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Pharmacology University of Toronto
© Copyright by Megan Joyce Shram (2008)
ABSTRACT
AGE DIFFERENCES IN THE VULNERABILITY TO NICOTINE ADDICTION: EVIDENCE FROM A RAT MODEL OF ADOLESCENT NICOTINE TAKING
Doctor of Philosophy (2008) Megan Joyce Shram Graduate Department of Pharmacology University of Toronto
Rationale: Peak initiation of smoking occurs during adolescence and early onset of smoking is associated with a reduced probability of quitting and greater risk of relapse compared to later onset. Considering the epidemiological evidence, adolescents may exhibit a unique biological susceptibility to nicotine taking, in addition to the behavioural and psychosocial factors known to influence adolescent smoking. Objectives: The current series of experiments, using a rat model of adolescent nicotine taking, was designed to investigate age differences in the processes involved in the acquisition and maintenance of nicotine taking that might account for the elevated initiation rates of smoking during adolescence. Methods: We first investigated age differences in the neural response to acute nicotine administration using c-fos mRNA expression. We then examined age differences in the rewarding and aversive effects of nicotine in the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. The direct reinforcing effects of nicotine were tested in adolescent and adult rats under a variety of reinforcement schedules in the operant intravenous self-administration
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paradigm; extinction and nicotine priming-induced reinstatement were also examined. Finally, age differences in nicotine withdrawal precipitated by mecamylamine were assessed. Results: Nicotine had greater activational effects on c-fos mRNA expression in reward-related neural substrates of adolescent compared to adult brain. Adolescent rats were also more sensitive to the rewarding effects of nicotine (CPP) yet less sensitive to its aversive effects (CTA) compared to adult rats. Nicotine was equally reinforcing in adolescents and adults self-administering under simple reinforcement schedules, but adults were more motivated to obtain nicotine under higher reinforcement schedules. Adults were more resistant to extinction, yet both age groups demonstrated similar priming-induced reinstatement of nicotine seeking. Under spontaneous acquisition conditions, adults were more sensitive to the reinforcing effects of a low nicotine infusion dose. The aversive effects of nicotine withdrawal were also more prominent in adults compared to adolescents. Conclusions: These findings have important implications since they demonstrate a unique susceptibility to the conditioned rewarding effects of nicotine that would promote acquisition of smoking behaviour during adolescence, whereas adults may be more vulnerable to processes involved in its maintenance.
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ACKNOWLEDGEMENTS Thank you to my supervisor, Dr. A.D. Lê, for providing me with guidance and support during my doctoral training; I must also thank you for always challenging me. I would like to extend my appreciation to my supervisory committee, Dr. Paul Fletcher, Dr. José Nobrega and Dr. Rachel Tyndale; your diverse and widespread expertise has helped me view my research findings not only from different perspectives, but also to focus my attention upon the most important issues. I must also thank Dr. Francesco Leri, Dr. Usoa Busto and Dr. Martin Zack for their time and critical appraisal of the thesis. I am incredibly grateful to Zhaoxia Li, who has provided so much support over the last four years; I certainly could not have accomplished so much without you. I also thank Dr. Douglas Funk, Stephen Harding, Walter Juzytsch, Kathy Coen, James Ennis and Casey Suchit for their help and experimental support.
I would like to thank the following funding agencies for the scholarships awarded to me during my doctoral training: Natural Sciences and Engineering Research Council, the Canadian Institute for Health Research Tobacco Use in Special Populations, the Canadian Tobacco Control Research Initiative and the University of Toronto.
And last, but certainly not least, I would like to thank my family for their never ending support. You have helped me accomplish so much both academically and in life and I am incredibly grateful for your constant encouragement.
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TABLE OF CONTENTS ABSTRACT.................................................................................................................................. II ACKNOWLEDGEMENTS ....................................................................................................... IV TABLE OF CONTENTS ............................................................................................................ V LIST OF PUBLICATIONS ........................................................................................................ X SUMMARY OF ABBREVIATIONS ........................................................................................ XI LIST OF TABLES .................................................................................................................... XII LIST OF FIGURES .................................................................................................................XIII STATEMENT OF RESEARCH PROBLEM ............................................................................ 1 CHAPTER 1 INTRODUCTION ................................................................................................. 3 SECTION 1 CIGARETTE SMOKING IN ADOLESCENCE: INITIATION, CORRELATES AND CONSEQUENCES ................................................................................. 3 SECTION 2 FACTORS ASSOCIATED WITH SMOKING DURING ADOLESCENCE... 4 SECTION 2.1 PSYCHOSOCIAL AND ENVIRONMENTAL FACTORS ASSOCIATED WITH SMOKING DURING ADOLESCENCE........................................................................ 5 SECTION 2.2 BEHAVIOURAL AND BIOLOGICAL FACTORS ASSOCIATED WITH SMOKING DURING ADOLESCENCE .................................................................................... 8 SECTION 3 ADOLESCENCE: MORE THAN A TRANSITION TO ADULTHOOD ...... 12 SECTION 3.1 AGE..................................................................................................................... 13 SECTION 3.2 REPRODUCTIVE MATURITY AND PHYSICAL GROWTH................... 13 SECTION 3.3 BEHAVIOURAL CHANGES ASSOCIATED WITH ADOLESCENCE.... 15 Section 3.3.1. Risk taking ............................................................................................................. 15 Section 3.3.2. Social behaviour..................................................................................................... 16 Section 3.3.3. Cognitive development .......................................................................................... 17 SECTION 3.4 NEURAL DEVELOPMENT ............................................................................ 18 Section 3.4.1. Gross neural changes ............................................................................................. 19
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Section 3.4.2. Alterations in neurotransmitter systems during adolescence................................. 20 SECTION 4 PHARMACOLOGY OF NICOTINE ................................................................. 23 SECTION 4.1 PHARMACOKINETICS .................................................................................. 23 SECTION 4.2 PHARMACODYNAMIC ACTION OF NICOTINE IN THE BRAIN ........ 25 SECTION 5 ANIMAL MODELS OF NICOTINE ADDICTION ......................................... 27 SECTION 5.1 EXPERIMENTAL MODELS OF DRUG TAKING ...................................... 27 Section 5.1.1. Conditioned place preference ................................................................................ 29 Section 5.1.2. Conditioned taste avoidance .................................................................................. 33 Section 5.1.4. Intravenous drug self-administration ..................................................................... 33 SECTION 5.2 EXPERIMENTAL MODELS OF DEPENDENCE AND RELAPSE .......... 36 Section 5.2.1. Dependence and withdrawal .................................................................................. 36 Section 5.2.2. Extinction and reinstatement: an animal model of relapse .................................... 38 SECTION 5.3 REINFORCING EFFECTS OF NICOTINE: EVIDENCE FROM ANIMAL MODELS ..................................................................................................................................... 39 SECTION 5.4 NICOTINE WITHDRAWAL AND RELAPSE TO NICOTINE SEEKING: EVIDENCE FROM ANIMAL MODELS ................................................................................ 42 SECTION 6 SUSCEPTIBILITY TO DRUGS OF ABUSE DURING ADOLESCENCE: EVIDENCE FROM ANIMAL MODELS ................................................................................ 43 SECTION 6.1 ALCOHOL AND OPIOIDS ............................................................................. 44 SECTION 6.2 PSYCHOSTIMULANTS .................................................................................. 45 SECTION 7 SUSCEPTIBILITY TO NICOTINE DURING ADOLESCENCE: EVIDENCE FROM ANIMAL MODELS ...................................................................................................... 47 SECTION 8 EXPERIMENTAL RATIONALE....................................................................... 49 Section 8.1 Rationale for investigating the effect of acute nicotine administration on c-fos mRNA expression in adolescent and adult rat brain ................................................................................. 50 Section 8.2 Rationale for investigating age differences in the conditioned rewarding and aversive effects of nicotine in adolescent and adult rats ............................................................................. 51
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Section 8.3 Rationale for investigating age differences in the direct reinforcing effects of nicotine and relapse-provoking effects of re-exposure to nicotine............................................................. 53 Section 8.4 Rationale for investigating age differences in the spontaneous acquisition of nicotine self-administration ........................................................................................................................ 54 Section 8.5 Rationale for investigating age differences in the motivational effects of mecamylamine-precipitated nicotine withdrawal ......................................................................... 55 CHAPTER 2: ACUTE NICOTINE ENHANCES C-FOS MRNA EXPRESSION DIFFERENTIALLY IN REWARD-RELATED SUBSTRATES OF ADOLESCENT AND ADULT RAT BRAIN ................................................................................................................. 57 Abstract ......................................................................................................................................... 58 Introduction................................................................................................................................... 59 Materials and Methods.................................................................................................................. 61 Results........................................................................................................................................... 64 Discussion ..................................................................................................................................... 69 Significance of chapter ................................................................................................................. 74 CHAPTER 3: ADOLESCENT AND ADULT RATS RESPOND DIFFERENTLY IN TESTS MEASURING THE REWARDING AND AVERSIVE EFFECTS OF NICOTINE ....................................................................................................................................................... 77 Abstract ......................................................................................................................................... 78 Introduction................................................................................................................................... 79 Materials and Methods.................................................................................................................. 83 Results........................................................................................................................................... 87 Discussion ..................................................................................................................................... 93 Significance of chapter ................................................................................................................. 99 CHAPTER 4: NICOTINE SELF-ADMINISTRATION, EXTINCTION RESPONDING AND REINSTATEMENT IN ADOLESCENT AND ADULT MALE RATS: EVIDENCE AGAINST A BIOLOGICAL VULNERABILITY TO NICOTINE ADDICTION DURING ADOLESCENCE ...................................................................................................................... 100 Abstract ....................................................................................................................................... 101 Introduction................................................................................................................................. 102 vii
Materials and Methods................................................................................................................ 104 Results......................................................................................................................................... 110 Discussion ................................................................................................................................... 121 Significance of chapter ............................................................................................................... 128 CHAPTER 5: AGE DIFFERENCES IN THE SPONTANEOUS ACQUISITION OF NICOTINE SELF-ADMINISTRATION IN MALE WISTAR AND LONG EVANS RATS ..................................................................................................................................................... 129 Abstract ....................................................................................................................................... 130 Introduction................................................................................................................................. 131 Materials and Methods................................................................................................................ 134 Results......................................................................................................................................... 139 Discussion ................................................................................................................................... 152 Significance of chapter ............................................................................................................... 160 CHAPTER 6: ADOLESCENT AND ADULT RATS RESPOND DIFFERENTLY TO THE AVERSIVE EFFECTS OF MECAMYLAMINE-PRECIPITATED WITHDRAWAL.... 161 Abstract ....................................................................................................................................... 162 Introduction................................................................................................................................. 163 Materials and Methods................................................................................................................ 165 Results......................................................................................................................................... 169 Discussion ................................................................................................................................... 175 Significance of chapter ............................................................................................................... 180 CHAPTER 7 GENERAL DISCUSSION................................................................................ 181 SECTION 9 AGE DIFFERENCES IN FACTORS INFLUENCING ACQUISITION OF NICOTINE TAKING ............................................................................................................... 182 SECTION 9.1 PARADOXICAL FINDINGS IN AGE DIFFERENCES IN THE REWARDING EFFECTS OF NICOTINE ............................................................................ 184 SECTION 9.2 AGE DIFFERENCES IN THE MOTIVATION TO SELF-ADMINISTER NICOTINE ................................................................................................................................ 186
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Section 9.2.1. Age differences in the motivation to self-administer nicotine: Potential role for dopamine..................................................................................................................................... 187 SECTION 9.3 AGE DIFFERENCES IN THE SENSITIVITY TO NICOTINE ................ 193 SECTION 9.4 DEVELOPMENTAL DIFFERENCES IN COGNITION AND POSSIBLE INTERACTIONS WITH NICOTINE .................................................................................... 195 SECTION 9.5 PHARMACOKINETIC DIFFERENCES ..................................................... 198 SECTION 9.6 AGE DIFFERENCES IN THE EFFECTS OF NICOTINE WITHIN THE CONTEXT OF ADOLESCENT SUSCEPTIBILITY TO DRUGS OF ABUSE ................ 200 SECTION 10 AGE DIFFERENCES IN FACTORS INFLUENCING MAINTENANCE OF NICOTINE TAKING ............................................................................................................... 201 SECTION 10.1 AGE DIFFERENCES IN NICOTINE WITHDRAWAL .......................... 201 SECTION 10.2 AGE DIFFERENCES IN NICOTINE WITHDRAWAL: POTENTIAL ROLE FOR REGION-DEPENDENT UPREGULATION OF NICOTINIC RECEPTORS ..................................................................................................................................................... 203 SECTION 10.3 AGE DIFFERENCES IN THE SUSCEPTIBILITY TO RELAPSE ........ 204 SECTION 10.4 CONCLUSIONS AND LIMITATIONS ...................................................... 205 SECTION 10.5 FUTURE WORK ........................................................................................... 210 Section 10.5.1. Age differences in the motivation to self-administer nicotine: Role for dopamine ..................................................................................................................................................... 211 Section 10.5.2. Interactions between stress and nicotine during adolescence ............................ 212 Section 10.5.3. Long-term effects of nicotine on HPA axis and NE function: Subsequent responses to nicotine ................................................................................................................... 214 REFERENCES.......................................................................................................................... 216 APPENDIX A: ADDITIONAL DATA ................................................................................... 253 Data not shown in Chapter 3: Adolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine ................................................................................. 253 Adolescent exposure to nicotine facilitates nicotine self-administration during adulthood ....... 254
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LIST OF PUBLICATIONS Shram, M.J., Z. Li and A.D. Lê (2007). Age differences in the spontaneous acquisition of nicotine self-administration: Implications for vulnerability to nicotine addiction during adolescence. Psychopharmacology, accepted. Shram, M.J., D. Funk, Z. Li and A.D. Lê (2007). Nicotine self-administration, extinction responding and reinstatement in adolescent and adult male rats: evidence against a biological vulnerability to nicotine addiction during adolescence. Neuropsychopharmacology, Epub May 16. Shram, M.J., D. Funk, Z. Li and A.D. Lê (2007). Acute nicotine enhances c-fos mRNA expression differentially in reward-related substrates of adolescent and adult rat brain. Neuroscience Letters, 418: 286-291. Shram, M.J., D. Funk, Z. Li and A.D. Lê (2006). Periadolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine. Psychopharmacology, 186: 201-208. Lê, A.D., Z. Li, D. Funk, M. Shram, T.K. Li and Y. Shaham (2006). Increased vulnerability to nicotine self-administration and relapse in alcohol-naïve offspring of rats selectively bred for high alcohol intake. Journal of Neuroscience, 26: 1872-1879.
SUBMITTED OR IN PREPARATION Shram, M.J., E.C.K. Siu, Z. Li, R.F. Tyndale and A.D. Lê. Adolescent and adult rats respond differently to the aversive effects of mecamylamine-precipitated nicotine withdrawal. Submitted to Psychopharmacology. Shram, M.J., and A.D. Lê. Adolescent rats are more susceptible to the rewarding effects of intravenously administered nicotine in the place conditioning paradigm. In preparation. Shram, M.J., W. Juzytsch and A.D. Lê. Adolescent pre-exposure to nicotine facilitates nicotine, but not alcohol self-administration. In preparation.
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SUMMARY OF ABBREVIATIONS
5-HT ACh BNST BP CeA CPA CPP CR CS DA DAT FR GABA ICSS LC LDT LS MFC MS NACc NACs nAChR NE NMDA PD PFC PPT PR PVN SES US VTA
serotonin acetylcholine bed nucleus of the stria terminalis breakpoint central amygdala conditioned place aversion conditioned place preference conditioned response conditioned stimulus dopamine dopamine transporter fixed ratio gamma-aminobutyric acid intracranial self-stimulation locus coeruleus laterodorsal tegmental nucleus lateral septum medial frontal cortex medial septum core region of the nucleus accumbens shell region of the nucleus accumbens nicotinic acetylcholinergic receptor norepinephrine/noradrenergic N-methyl-d-aspartate postnatal day prefrontal cortex pedunculopontine tegmental nucleus progressive ratio paraventricular nucleus of the hypothalamus socioeconomic status unconditioned stimulus ventral tegmental area
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LIST OF TABLES
Table 1. Factors important in the initiation and maintenance of smoking behaviour during adolescence, p. 6. Table 2. Effect of nicotine on c-fos mRNA in adolescent and adult rat brain, p. 64. Table 3. ANOVA results from the analyses of individual brain regions, p. 65. Table 4. Saccharin self-administration in adolescent and adult rats, p. 117. Table 5. Proportion of rats acquiring nicotine and saccharin self-administration, p. 140.
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LIST OF FIGURES
Figure 1. Schematic diagram of the processes involved in the experimentation, initiation and maintenance of drug taking behaviour, e.g., smoking, p. 29. Figure 2. Effect of acute nicotine administration on the activation of c-fos mRNA expression, p. 67. Figure 3. Place conditioning to nicotine in adolescent and adult male Wistar rats, p. 87. Figure 4. Locomotor activity during the nicotine place conditioning study in adolescent and adult male Wistar rats, p. 88. Figure 5. Conditioned taste avoidance of a nicotine-paired solution in adolescent and adult male Wistar rats, p. 90. Figure 6. Extinction of a conditioned taste avoidance to a nicotine-paired saccharin solution in adolescent and adult male Wistar rats, p. 91. Figure 7. Nicotine self-administration in adolescent and adult rats during Experiment 1, p. 112. Figure 8. Nicotine self-administration in adolescent and adult rats during Experiment 2, p. 113. Figure 9. Extinction and reinstatement of nicotine seeking in rats that initiated nicotine selfadministration during adolescence and adulthood, p. 115. Figure 10. Saccharin self-administration under progressive ratio conditions in adolescent and adult rats, p. 118. Figure 11. Extinction of saccharin seeking in rats that initiated self-administration during adolescence and adulthood, p. 120. Figure 12. Spontaneous acquisition of nicotine self-administration in adolescent and adult male rats, p. 142. Figure 13. Nicotine infusions earned by adolescent and adult male rats spontaneously acquiring nicotine self-administration, p. 143. Figure 14. Extinction and priming-induced reinstatement of nicotine seeking in adolescent and adult male LE and Wistar rats, p. 146. Figure 15. Spontaneous acquisition of saccharin self-administration in adolescent and adult male rats, p. 149.
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Figure 16. Extinction and priming-induced reinstatement of saccharin seeking in adolescent and adult male LE and Wistar rats that acquired saccharin self-administration, p. 150. Figure 17. Mecamylamine-precipitated withdrawal place aversion in adolescent and adult rats chronically treated with 3 or 6 mg/kg/day nicotine, p. 170. Figure 18. Mecamylamine-precipitated physical signs of withdrawal in adolescent and adult rats chronically treated with 3 or 6 mg/kg/day nicotine, p. 171. Figure 19. Plasma nicotine levels in adolescent and adult rats chronically treated with 3 or 6 mg/kg/day nicotine, p. 172. Figure 20. Mecamylamine-precipitated withdrawal place aversion and physical signs of withdrawal in adolescents chronically treated with 4.5 or 9 mg/kg/day nicotine, p. 174. Figure 21. Water consumption during extinction of a conditioned taste avoidance to a nicotinepaired saccharin solution in adolescent and adult male Wistar rats, p. 253. Figure 22. Nicotine self-administration by rats pretreated with nicotine during adolescence or adulthood, p. 255. Figure 23. Active lever responding for nicotine by rats pretreated with nicotine during adolescence or adulthood p. 256. Figure 24. PR responding by rats pretreated with nicotine during adolescence or adulthood, p. 257. Figure 25. Reinforcing efficacy of nicotine in rats pretreated with nicotine during adolescence or adulthood, p. 258.
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STATEMENT OF RESEARCH PROBLEM
Tobacco smoking is the single most preventable cause of premature death and accounts for approximately one in five deaths in the United States and Canada (CDC, 2005; Peto et al., 2006). Peak initiation of smoking occurs during adolescence, suggesting that adolescence may be a unique period in the development of tobacco dependence. Early onset of smoking is associated with a more rapid progression to dependence, a reduced probability of quitting and increased risk of relapse compared to later onset of smoking. Furthermore, smoking during adolescence is also associated with an increased probability of alcohol and drug abuse and dependence, and therefore, may act as a gateway drug. Despite this epidemiological evidence, little is known about a potential biological susceptibility to nicotine, the psychoactive substance found in tobacco, and its withdrawal that may account for the high initiation rates and persistence of smoking behaviour during the adolescent period. A systematic investigation of the processes involved in the initiation and maintenance of nicotine taking would provide valuable evidence for the enhanced vulnerability hypothesis. Due to ethical constraints in examining this issue in humans, an animal model is a useful tool to investigate such a potential biological susceptibility to the motivational effects of nicotine and can control for environmental and psychosocial factors demonstrated to be important in the initiation of smoking, such as peer pressure and perceptions of smoking. The adolescent rat provides a ready model to examine the adolescent response to nicotine. Early evidence suggests that adolescent rats are more responsive to nicotine’s rewarding effects compared to adult rats, however the degree to
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which this reflects an enhanced vulnerability remains to be answered. The enhanced vulnerability to nicotine taking in adolescence is of widespread interest as it may help explain the greater initiation rates and the long-term implications associated with adolescent onset of smoking. To address the hypothesis of a biological susceptibility to nicotine in adolescence, we compared the response of adolescent and adult rats in tests measuring the processes involved in acquisition and maintenance of nicotine taking behaviour.
2
CHAPTER 1 INTRODUCTION
SECTION 1 CIGARETTE SMOKING IN ADOLESCENCE: INITIATION, CORRELATES AND CONSEQUENCES
Initiation of smoking typically occurs during adolescence, traditionally defined as the period between 12 and 18 years of age, with peak initiation occurring between 11 and 13 years of age (Johnston et al., 2001; Johnston et al., 2006). In Canada, almost 90% of current adult smokers began smoking by age 20 (Health Canada, 2003) and in the US, 76% of smokers initiated use by age 18 (SAMHSA, 2003), providing further evidence that the majority of smoking initiation occurs during adolescence. Approximately four thousand adolescents initiate smoking and over one thousand become daily cigarette smokers each day in the US (SAMHSA, 2005). Currently, 16% of Canadian adolescents (Health Canada, 2006a) and 23% of US adolescents (CDC, 2006a) between the ages of 15 and 19 are current smokers, with global prevalence rates of tobacco use among 13 to 15 year olds within the same range (17.3% across 132 countries; CDC, 2006b). In addition to increased morbidity and mortality (CDC, 1996; Peto et al., 2006) , early onset of smoking is associated with a number of short- and long-term correlates and consequences. In the more immediate timeframe, those who have tried smoking in grades 7 to 9 (12-15 years old) are more likely to drink alcohol (91.2%), binge drink (58.5%) and try cannabis (50.3%) compared to those who have not tried smoking (52.5, 22.8 and 4.7%, respectively) (Health Canada, 2006b). These data suggest that cigarette smoking may be a marker or a specific feature of adolescent problem behaviours (Jessor and Jessor, 1977; Willard and Schoenborn, 1995; Coogan et al., 1998; Hanna et al., 2001). Alternatively, 3
cigarette smoking may be a gateway to other licit and illicit drug use in that it facilitates the progression to hazardous use of other abused drugs (e.g., Kandel and Faust, 1975; Henningfield et al., 1990; Kandel and Yamaguchi, 1993; Vega and Gil, 2005). Early onset of smoking is also associated with heavier smoking (Chen and Millar, 1998; Everett et al., 1999), a more rapid progression to nicotine dependence (Colby et al., 2000) a reduced probability of quitting smoking in adulthood (Breslau and Peterson, 1996) and greater probability of relapse (Cui et al., 2006). Although males are more likely to initiate smoking prior to age 13 (Grant and Dawson, 1998; Hanna and Grant, 1999), the influence of such early onset of smoking may be more marked in females than males in terms of cessation (Chen and Millar, 1998) and heavy smoking (Fernandez et al., 1999) in adulthood. On the other hand, onset of smoking up to age 20 in males confers a reduced probability of quitting compared to those who began smoking after age 20 (Chen and Millar, 1998).
SECTION 2 FACTORS ASSOCIATED WITH SMOKING DURING ADOLESCENCE
Studies of tobacco use in adolescence indicate the presence of multiple factors influencing the initiation and maintenance of smoking behaviours. Adolescent onset of smoking, and early onset in particular, is associated with a number of factors that are 1) psychosocial/environmental and 2) behavioural/biological in nature (see Table 1). Social and environmental influences appear to be stronger in younger adolescents, yet genetic and personality influences become more substantial with age and are more predictive of use in later adolescence (Hopfer et al., 2003).
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SECTION 2.1 PSYCHOSOCIAL AND ENVIRONMENTAL FACTORS ASSOCIATED WITH SMOKING DURING ADOLESCENCE A number of sociodemographic factors have been associated with smoking during adolescence, including age, ethnicity, family structure and socioeconomic status. Experimentation and initiation of smoking typically begin in early adolescence and peak between 12 and 16 years of age and leveling off thereafter (Johnston et al., 1998). Ethnic background also influences smoking behaviour: Hispanic (11%) and White (16%) adolescents exhibit similar smoking rates, Black (7%) and Asian (8%) adolescents report the lowest, whereas Native American adolescents (28%) consistently show the highest prevalence rates. Although prevalence of smoking varies across ethnic groups, the age at initiation is similar (Caraballo et al., 2006). As in the adult population, lower socioeconomic status is associated with an increased likelihood of smoking, as is lower parental education (Wills et al., 2004). Family structure is also an important factor, with an intact family conferring protection against smoking compared to divorced or blended families (Wills et al., 1996). Social environment exerts a significant influence on the probability of initiating and experimenting with smoking. Smoking is a learned behaviour that is influenced by the actions and beliefs of others, including family and peers, with the presence of smoking models promoting tolerance to smoking (Poulsen et al., 2002). Parental smoking has a modest effect on the initiation of smoking (Boomsma et al., 1994; Avenevoli and Merikangas, 2003), but may be a better predictor of daily smoking (Hill et al., 2005). In contrast, peer smoking has a remarkable influence on initiation, experimentation, current and ever use (Rose et al., 1999b) and appears strongest between 12 and 15 years of age (Flay et al., 1994; Tyas and Pederson, 1998; Hoffman et al., 2006; Kokkevi et al., 2007). 5
The greater influence of peers may be associated with the increased time spent with smoking friends who normalize the behaviour (Conrad et al., 1992; Flay et al., 1998).
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Table 1. Factors important in the initiation and maintenance of smoking behaviour during adolescence Psychosocial/Environmental Effect Sample references Age
early age ↑
Johnston et al., 1998
Ethnicity
Caucasian, Hispanic, Native American ↑ African-American, Asian ↓ low SES ↑ ↑ initiation ↑↑ daily smoking
Tyas and Pederson, 1998
Peer smoking
↑↑ initiation, experimentation, current use
Flay et al., 1994; Rose et al., 1999
Attitudes/perceptions
↑ if positive beliefs; little impact of knowledge of negative effects of smoking
Chassin et al., 1984; Dalton et al., 1999
Impulsivity
↑ risk
Dinn et al., 2004
Risk taking
↑ risk
Lewinsohn et al., 2000
Novelty seeking
↑ risk
Lynskey et al., 1998
Academic performance
↑ if poor performance
Willard and Schoenberg, 1995
Psychopathology
e.g., depression, attention deficit hyperactivity disorder; directionality of effect?
Windle and Windle, 2001; Lynskey and Hall, 2001; Chambers et al., 2003
Genetics
↑ initiation ↑↑ amount smoked
Hopfer et al., 2003; Koopmans et al., 1999
Nicotine metabolism
↑ risk of dependence if slow metabolizer (CYP2A6*2,*4), but more rapid progression if normal metabolizer ↑ if sensitive to nausea/dizziness/relaxation
O'Loughlin et al., 2004; Audrain-McGovern et al., 2007
Socioeconomic status (SES) Parental smoking
Wills et al., 2004 Avenevoli and Merikangas, 2003; Hill et al., 2005
Behavioural/Biological
Sensitivity to nicotine Sensitivity to nicotine tolerance/ withdrawal
↑ smoking/reduced cessation
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Riedel et al., 2003; DiFranza et al., 2004 Burt and Peterson, 1998; Colby et al., 2000
Intermediate in influence is smoking by siblings, which has been shown to be a consistent risk factor for current and lifetime smoking during adolescence (Avenevoli and Merikangas, 2003). Other important determinants of smoking initiation and daily smoking include family relations, parental monitoring and home smoking rules (van den Bree et al., 2004; Hill et al., 2005; Clark et al., 2006).
SECTION 2.2 BEHAVIOURAL AND BIOLOGICAL FACTORS ASSOCIATED WITH SMOKING DURING ADOLESCENCE Personality traits including impulsivity, risk taking and sensation/novelty seeking are important predictors of experimental and current smoking (Lynskey et al., 1998; Tyas and Pederson, 1998; Lewinsohn et al., 2000; Dinn et al., 2004). Furthermore, increased rebelliousness, low academic performance and poor school behaviour are associated with initiation and progression of smoking behaviour (Willard and Schoenborn, 1995; Coogan et al., 1998; Lewinsohn et al., 2000; Dinn et al., 2004; van den Bree et al., 2004). Attitudes, perceptions and knowledge of smoking also influence the probability of smoking during adolescence. Having positive expectancies related to tobacco use increases the probability of initiation and progression to regular smoking (Chassin et al., 1984; Dalton et al., 1999). A lack of concern about the health consequences of smoking also predicts initiation and thus, knowledge of the negative effects of smoking does not appear to be a very good predictor of future smoking (Botvin et al., 1992). Personal factors including self-esteem, affect and coping strategies are important determinants of smoking during adolescence. Whereas self-esteem and active coping act as protective factors (Conrad et al., 1992), higher negative affect, lower positive affect and avoidant coping strategies increase the probability of smoking (Coogan et al., 1998; 8
Whalen et al., 2001; Wills et al., 2004). Decision-making skills, which mature during adolescence, also influence susceptibility to smoking. Knowledge of health issues may deter an individual from smoking, however immature decision-making skills may lead to discounting of the long-term health effects for the immediate benefits associated with smoking, e.g., acceptance by peers, feeling high (Slovic, 2000; Byrnes, 2002). Increased susceptibility to smoking is also related to psychopathology. Compared to never smokers, current or former adolescent smokers are more likely to have a diagnosis of major depressive disorder, anxiety, attention deficit hyperactivity disorder, conduct problems and alcohol or drug dependence (Coogan et al., 1998; Lynskey et al., 1998; Lynskey and Hall, 2001; Windle and Windle, 2001). Interestingly, smoking is more closely associated with externalizing disorders (Dinn et al., 2004), whose pathologies are more closely linked to deficits in the dopamine (DA) system, a neurotransmitter system implicated in the motivational effects of drugs of abuse. Tobacco use in adolescence appears to be under strong genetic control, even more so than alcohol or other drug use (Hopfer et al., 2003). Heritability studies in adolescent twins indicate tobacco use and problem use have moderate heritability with small shared environmental effects (Han et al., 1999; Maes et al., 1999; McGue et al., 2000; Young et al., 2006). More specifically, initiation of smoking is moderately heritable (39%) and quantity smoked shows substantial heritability (86%), as assessed in a study of twins aged 12 to 24 (mean age = 17.7 years, Koopmans et al., 1999). However, a study in which the sample was stratified by age indicated that genetic factors were less important determinants of ever smoking in 12 to 16 year olds compared to 17 to 25 year olds (Koopmans et al., 1997). Interestingly, genetic variability in nicotine metabolism is associated with different
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profiles of smoking behaviour. In adults, slow metabolizers smoke fewer cigarettes and are less likely to be smokers (Tyndale and Sellers, 2002; Schoedel et al., 2004). However, these genetic differences appear to play a different role in the initiation of smoking, with slow nicotine metabolizers exhibiting an increased risk of initiating smoking at a younger age and developing nicotine dependence compared to normal nicotine metabolizers, despite smoking fewer cigarettes (O'Loughlin et al., 2004). Progression to dependence during adolescence however, may be more rapid in normal metabolizers (Audrain-McGovern et al., 2007). Other biological factors associated with the susceptibility to smoking include factors related to the addiction process, such as sensitivity to the rewarding and aversive effects of nicotine during the initial experimental stages, the development of tolerance and dependence to the effects of nicotine, and withdrawal effects upon abstinence from smoking. The first experience with smoking can be aversive, with coughing, chest irritation and nausea being the most commonly reported aversive symptoms. The pleasurable effects of smoking, including relaxation and dizziness, are predictors of continued use (Pomerleau et al., 1998). However, nausea is also an independent predictor of developing nicotine dependence, which suggests that initial sensitivity to the effects of nicotine, be they aversive or rewarding, may be most influential in the likelihood of continued smoking (Pomerleau et al., 1993; DiFranza et al., 2004). Daily smoking is not necessary for adolescents to exhibit symptoms of dependence, e.g., tolerance, cravings, unsuccessful attempts to cut down and withdrawal symptoms upon abstinence (DiFranza et al., 2000; O'Loughlin et al., 2003). Therefore, even in the
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early phases of smoking, dependence factors are important in the process of continued smoking behaviour. Effects of withdrawal from smoking are a common reason for relapse to smoking. Although adolescents have only had a short history of exposure to smoking, many are unable to maintain abstinence (e.g., 24 months, Okamoto et al., 1994).
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SECTION 4.2 PHARMACODYNAMIC ACTION OF NICOTINE IN THE BRAIN Nicotine preferentially binds to nAChRs, which are found in the brain, autonomic ganglia and neuromuscular junction (Benowitz, 1996). The neuronal nAChR is a ligandgated ion channel comprising a pentameric subunit composition. There are numerous subunit types (α2-10 and β2-4) whose configurations produce a wide variety of nAChR subtypes (Gotti and Clementi, 2004). Regional expression of different receptor subtypes is heterogeneous and their pre- and post-synaptic locations are important in the observed behavioural responses to nicotine (Matta et al., 2007). The nAChR is intriguing and unique in that it undergoes numerous allosteric changes following binding resulting in a variety of states, including a resting, activated (open channel) and two desensitized states (closed channel, Benowitz, 1996). Tolerance to nicotine is paradoxically related to an upregulation of nAChRs, which may be related to reduced turnover rates rather than synthesis of new receptors (Madhok et al., 1994). Neuronal nAChRs are located on the cell bodies and nerve terminals of many types of neurons (Paterson and Nordberg, 2000) and their activation promotes the release of neurotransmitters including DA, ACh, NE and 5-HT. Nicotine preferentially increases the release of DA over 5-HT and NE, and does so at lower doses (Singer et al., 2004). This preferential action on DA release is important in the reinforcing effects of nicotine. In rats, nicotine self-administration results in DA release within the NAC (Lecca et al., 2006) and DA receptor blockade via pharmacological antagonism dose-dependently reduces nicotine self-administration (Corrigall and Coen, 1991). This effect is likely mediated by a nAChRdependent mechanism since mecamylamine, a non-competitive nAChR antagonist, also reduces self-administration and the DA response to nicotine (Watkins et al., 1999; Sziraki
25
et al., 2002; DeNoble and Mele, 2006). Evidence that the α4β2 subtype of nAChR contributes to the reinforcing effects of nicotine include the observations that dihydro-betaerythroidine, an antagonist selective for the α4 subunit, reduces nicotine self-administration (Watkins et al., 1999) and β2 knockout mice show weak nicotine self-administration compared to wild-type mice (Picciotto et al., 1998). This receptor subtype is also implicated in the withdrawal and antinociceptive effects of nicotine (Marubio et al., 1999; Salas et al., 2004). The reinforcing action of nicotine is thought to be mediated primarily by its action on the mesocorticolimbic DA system, an effect similar to that of other drugs of abuse (Di Chiara and Imperato, 1988). Stimulation of nAChRs located on ventral tegmental area (VTA) dopaminergic cell bodies activates neurons projecting to the NAC (Pidoplichko et al., 1997; Pidoplichko et al., 2004) and nicotine applied directly to the VTA increases DA release in NAC (Yoshida et al., 1993). Intra-VTA administration of nAChR antagonists attenuates nicotine self-administration, indicating that stimulation of nAChR located in the VTA is necessary for nicotine’s reinforcing effects (Corrigall and Coen, 1989; Corrigall et al., 1994; Ikemoto et al., 2006). nAChRs in NAC are also important, however those in the VTA play a larger role in mediating nicotine self-administration (Corrigall et al., 1994; Nisell et al., 1994b, 1994a). Furthermore, 6-hydroxydopamine lesions of the NAC and administration of DA antagonists reduces nicotine self-administration, supporting a role for DA in reinforcing nicotine self-administration (Corrigall and Coen, 1991; Corrigall et al., 1992). The pedunculopontine (PPT) and laterodorsal tegmenta (LDT) are also important nuclei implicated in the reinforcing action of nicotine. The PPT and LDT provide important cholinergic projections to the VTA, with lesions of the PPT disrupting nicotine self-
26
administration (Lanca et al., 2000a) and lesions of the LDT reducing VTA-mediated DA release in the NAC (Blaha et al., 1996). Nicotine dose-dependently increases DA release in ventral and dorsal striata, and age differences in potency have recently been reported (Azam et al., 2007). Compared to adult striatal samples, nicotine is less potent at PD30 and more potent at PD40 in its DA releasing action. Further to this, ventral striatal samples obtained from PD30 males exhibit a higher maximum nicotine-induced stimulation of DA release compared to other ages. This may suggest that, although the threshold to stimulate DA release is higher at PD30, the subsequent DA (and possibly behavioural response) to nicotine would be more pronounced in these younger adolescents. Much emphasis has been placed on DA’s role in mediating the reinforcing actions of nicotine, but other neurotransmitters are also involved in the effects of nicotine, including GABA and glutamate (e.g., Corrigall et al., 2001; Kashkin and De Witte, 2005).
SECTION 5 ANIMAL MODELS OF NICOTINE ADDICTION SECTION 5.1 EXPERIMENTAL MODELS OF DRUG TAKING Although much discussion has been generated over its definition, drug addiction may be described as “a behavioural pattern of compulsive use, characterized by overwhelming involvement with the use of a drug, the securing of its supply, and a high tendency to relapse after withdrawal” (Jaffe, 1975). The use of a drug does not necessarily entail drug addiction, however the rewarding and reinforcing effects of drugs are a primary determinant of drug taking behaviour and are an important area of study. Different factors likely mediate initiation, acquisition and maintenance of drug taking (Bozarth, 1990). Initial use or approach is most likely related to expectancies, 27
curiosity, peer pressure and personality traits such as impulsivity and sensation seeking. Once consumed, the pharmacological effects of a drug play a modulatory role in the likelihood of continued drug taking, but non-drug factors remain influential in this early phase of drug taking behaviour. Following acquisition, maintenance of drug taking is associated with a shift from personal and environmental factors to pharmacological factors that guide drug taking behaviours. The motivational effects of the drug and cues associated with the drug effects are enhanced with repeated use, eventually leading to regular and possibly compulsive use. In the early stages of use, drugs serve as positive reinforcers that increase approach responses and maintain drug taking behaviours (Stolerman, 1992). There has been much debate over the terms ‘reward’ and ‘reinforcement’ in the psychology of drug addiction literature (e.g., White, 1989), and so a brief operational definition of each is presented here. Reward is any stimulus that elicits an approach response, however, reinforcement is a process by which the probability of a behaviour increases or decreases depending upon the immediate outcome or consequence of that behaviour. This process is based upon the principles of instrumental learning and does not depend upon the motivational valence of the stimulus. A reinforcer increases the probability of a response if the behaviour results in the delivery of a rewarding stimulus (a positive reinforcer), e.g., food, sex, drugs, or if it removes an aversive stimulus (a negative reinforcer), e.g., shock, drug withdrawal. In contrast, a punisher will reduce the probability of a response. The rewarding and reinforcing effects of a drug are critical for acquisition and maintenance of drug taking (Schenk and Partridge, 1997), but pleasure derived from the drug may decrease with compulsive use, with craving playing a more prominent role in
28
maintaining drug use and precipitating relapse (Robinson and Berridge, 1993). With prolonged use however, withdrawal and relapse become increasingly important in maintaining drug taking behaviour. Figure 1 depicts the factors and processes in drug taking behaviour, using smoking as an example. The processes involved in drug taking and compulsive use have undergone extensive examination using animal models. Animal models provide a means to assess the behavioural and neurobiological processes underlying drug addiction that may not readily be tested in humans due to ethical constraints and confounding variables (e.g., history of drug exposure). Under controlled conditions, animal models may be used to examine processes related to acquisition, maintenance, extinction and relapse to drug taking behaviours, as well as examine the influence of environmental, behavioural, developmental and neurobiological factors contributing to individual differences in vulnerability to drug taking (Koob, 2000). The models described here are proposed to measure the rewarding and reinforcing effects of drugs of abuse, including nicotine, that play an important role in the initiation of drug use, as well as the factors motivating continued use, e.g., withdrawal and relapse.
Section 5.1.1. Conditioned place preference The conditioned place preference (CPP) paradigm measures the relative rewarding and aversive effects of drugs of abuse (Tzschentke, 1998). CPP involves developing an association between distinct environmental cues (conditioned stimulus, CS) with which a drug (unconditioned stimulus, US) is paired through classical conditioning. More specifically, using a two-compartment CPP apparatus, drug administration (US) is paired with one compartment (CS) and vehicle is paired with the opposite compartment, which 29
Social Behavioural
Peer and family influences
Risk taking
Socioeconomic status
Attitudes, beliefs, perceptions
Impulsivity Sensation seeking
Strength of influence
Experimentation Primarily Environmental
Initial response to smoking Positive effects: dizziness, relaxation Negative effects: nausea, chest irritation, coughing
Initiation Primarily Pharmacological
Reinforcing efficacy
Maintenance
Genetics Coping
Tolerance/Sensitization
Psychopathology
Withdrawal Relapse re-exposure to nicotine smoking cues stress
Figure 1. Schematic diagram of the processes involved in the experimentation, initiation and maintenance of drug taking behaviour, e.g., smoking. Experimental use is primarily driven by environmental and psychosocial factors. With repeated use, pharmacological and genetic factors play increasingly significant roles in maintaining drug use, although environmental and psychosocial factors continue to influence drug taking behaviour. 30
can differ along visual, textural and olfactory dimensions. Following single or repeated pairings, the animal is then tested under drug-free conditions with access to both compartments. The time spent in the drug-paired compartment during the test (conditioned response, CR) provides an index of the rewarding (or aversive) effects of a drug. CPP has relatively good concordance with human drug abuse liability in that drugs that are used in humans can elicit CPP in animals. A notable exception is alcohol, which typically produces a conditioned place aversion (CPA), particularly in rats (e.g., Cunningham et al., 2003; Fidler et al., 2004; Funk et al., 2004), although it is readily consumed under voluntary selfadministration conditions (for reviews, see Cunningham et al., 2000; Samson and Czachowski, 2003). There are two methods commonly used in CPP experiments: biased and unbiased. Animals may spontaneously exhibit a preference (or aversion) to one compartment. Under the ‘biased’ condition, drug pairings occur in the initially non-preferred compartment because of ceiling effects that preclude the expression of a CPP in the initially preferred compartment (Cunningham et al., 2003). The biased procedure is more susceptible to false positive results since it is the relative increase in time spent in the drug-paired compartment that is being used to measure CPP (Tzschentke, 1998); this shift in preference may be attributable to the rewarding effects of the drug or possibly its anxiolytic effects. In order to accurately report a CPP, an absolute preference for the drug-paired compartment, i.e., >50% of time during the test, must be observed. The use of an ‘unbiased’ procedure eliminates the confounds associated with the biased method since there is no initial preference for either compartment prior to drug administration. Thus, a shift in
31
compartment preference would directly measure the rewarding or aversive effects of a drug, and as such, the unbiased procedure should be the method of choice in CPP experiments. The CPP paradigm is considered to be valuable as a preliminary screen for drug abuse liability. It offers a direct method of assessing the conditioned effects of a drug that are important in the control of drug taking behaviour (Bozarth, 1987). This procedure does not typically require surgery and is quick to administer; CPP can be observed following a single conditioning trial (Bardo and Neisewander, 1986; Bardo et al., 1999a; Spina et al., 2006), though most employ a repeated conditioning procedure as it is more robust. Testing occurs in a drug-free state and thus, potential motor impairing effects of a drug do not readily interfere with approach/avoidance behaviour of the animal. Other advantages include that CPP can be sensitive to low drug doses and the experimenter can control dosing and cues associated with the drug (Bardo and Bevins, 2000). However, dosedependent effects on CPP magnitude are not readily observed, and there is often an all-ornone response. Furthermore, only one datapoint per animal can be generated following multiple conditioning trials, and one cannot track the behaviour during conditioning. Face and construct validity are low (Olmstead, 2006; Sanchis-Segura and Spanagel, 2006) and drug exposure is passive, which is known to produce different effects compared to actively self-administered drug (Dworkin et al., 1995; Jacobs et al., 2003). While it is a valuable preliminary screen of the rewarding effects of a drug, CPP is insufficient on its own to demonstrate that a drug is addictive. Simply because animals are sensitive to the drug’s rewarding effects does not indicate that it is addictive. For example, Bardo and colleagues (1999a) have demonstrated that the magnitude of CPP does not
32
correlate with propensity to self-administer amphetamine. In combination with other experimental methods however, it is a powerful tool in identifying factors involved in the motivational effects of drugs.
Section 5.1.2. Conditioned taste avoidance The conditioned taste avoidance (CTA) paradigm is thought to measure the aversive effects of abused drugs through classical conditioning, and it is qualitatively distinct from the conditioned taste aversion elicited by noxious stimuli (Hunt and Amit, 1987; Parker, 1995). In this procedure, animals are allowed to consume an appetitive tastant (CS, typically sucrose or saccharin) under limited access conditions, following which the drug (US) is administered. Single or multiple CS-US pairings are followed by a preference test between water and the CS. Drugs of abuse reliably suppress consumption of the CS, indicating the induction of a CTA. The paradoxical finding that addictive drugs produce CPP, but also elicit a CTA has been subject to a number of interpretations, such as the reward contrast hypothesis (Grigson, 1997). This paradigm is quick to administer and is reliable, but similar to CPP, has low face validity.
Section 5.1.4. Intravenous drug self-administration Self-administration is the gold standard of assessing the direct reinforcing effects of drugs of abuse, since intake is voluntary and under control of the animal; this most closely approximates human drug taking behaviour. Both humans and animals will readily selfadminister drugs in a non-dependent state, indicating that the reinforcing effects of drugs can drive drug-taking behaviour (Koob, 2000). 33
The self-administration paradigm follows the principles of operant conditioning in that drug taking behaviours are mediated by their direct and immediate consequences, namely drug administration and associated pharmacological actions of the drug (Bozarth, 1990). Drugs serve as positive reinforcers by increasing the probability of the behaviour (e.g., lever pressing or nosepoking) upon which their presentation is contingent. In the intravenous self-administration paradigm, animals are first surgically prepared with chronic indwelling jugular catheters that will enable direct and rapid drug delivery to the animal. To facilitate drug self-administration, animals are traditionally first trained on the operant response using food as reinforcement. Self-administration typically occurs in an operant chamber equipped with two levers and discrete and environmental stimuli. Pressing on a lever, designated as active, results in the delivery of a set drug infusion; pressing on the inactive lever, which acts as a control for non-specific motor effects of the drug and whether the drug is controlling the behaviour, has no consequence (Gardner, 2000). self-administration sessions can vary in duration from one hour to continuous access, however limiting access to a discrete time period produces stable high drug intake and is a convenient model for assessing pharmacological manipulations in drug taking (Caine et al., 1993). Often, drug delivery is paired with a discrete cue, such as a light or tone stimulus, which acts as a predictor of drug availability and may develop conditioned reinforcing properties (Stewart et al., 1984; Caggiula et al., 2002). Such drug-cue associations are important in testing the motivational effects of discrete and environmental cues on drug taking behaviours (Stewart et al., 1984). The self-administration paradigm can be used to assess various processes involved in drug taking, including acquisition, maintenance and relapse behaviours. Spontaneous
34
acquisition of drug self-administration is a direct measure of the strength of a drug to reinforce operant behaviour. Drug naïve rats are placed in the operant chamber without prior training and initial contact with the drug is accidental. Through repeated pairings of the operant behaviour and subsequent drug delivery, the operant behaviour is established and drug taking increases progressively across sessions. Acquisition studies typically employ fixed ratio (FR) 1 or continuous reinforcement schedules, with one lever press resulting in the delivery of one drug infusion. This is one of the most common reinforcement schedules because it is the most easily acquired and is an important tool for screening initial abuse liability (Richardson and Roberts, 1996). However, it may be limited to a qualitative assessment of whether a drug serves as a positive reinforcer and may not be sensitive to changes in reinforcing efficacy. A more direct, quantitative, assessment of the reinforcing efficacy of a drug is to increase the work required to obtain the drug. One valid method is the progressive ratio (PR) reinforcement schedule in which increasing effort is required to obtain successive drug infusions (Richardson and Roberts, 1996; Stafford et al., 1998). PR testing may occur within or between sessions. The former procedure may be more useful and provides a more rapid assessment of reinforcing efficacy, though cumulative dosing during the PR session may interfere with drug taking behaviour. One way to circumvent this issue is to use a rapidly escalating schedule such that a high work requirement is necessary following a minimal number of drug infusions. Most schedules in current use are exponential in nature, and behaviour stabilizes quickly across few sessions (Depoortere et al., 1993). The measure typically used to assess the reinforcing efficacy of a drug is called the breakpoint (BP),
35
which is the largest ratio requirement an animal is willing to complete to obtain one infusion of the drug (Arnold and Roberts, 1997). The self-administration model possesses high face, construct and predictive validity and is reliable. It has good concordance with human drug taking, since drugs that support self-administration in animals also hold abuse liability in humans (Griffiths and Balster, 1979). Changes in dose produce reliable alterations in self-administration behaviour, indicating changes in reinforcing effects of different doses (Koob, 2000). Selfadministration performance is sensitive to low drug doses and animals will maintain stable blood/brain levels by behaviourally compensating for different drug doses. Important advantages of the self-administration paradigm are that administration is under the active control of the animal, discrete and environmental cues associated with drug taking behaviour can be controlled, and, unlike CPP, a within-subjects design can be used to generate data (Koob, 2000).
SECTION 5.2 EXPERIMENTAL MODELS OF DEPENDENCE AND RELAPSE Section 5.2.1. Dependence and withdrawal Alleviation of withdrawal symptoms is an important motivating factor in the continued use of abused drugs (Koob et al., 1997; Baker et al., 2004a; Eissenberg, 2004). In fact, early addiction research suggested that withdrawal was the driving force promoting and maintaining use, since the removal of an aversive withdrawal state associated with abstinence would reinforce drug taking behaviour. This is referred to as the negative reinforcement hypothesis of addiction (for brief review, see Robinson and Berridge, 1993). Considering this, much work has been devoted to developing animal models of dependence and withdrawal. In most dependence models, animals are treated with a drug over an 36
extended period of time either by a multiple drug administration procedure or through constant infusion, e.g., via osmotic minipumps or pellets, depending upon the drug, which yields stable drug levels and minimizes the potential confound of stress associated with repeated drug injections. Following extensive exposure to the drug, a number of withdrawal tests can be administered under spontaneous or antagonist-precipitated withdrawal conditions. Physical signs of withdrawal are most commonly and easily assessed by the experimenter. The expression of physical withdrawal signs is species typical and, in the rat, has been well-documented following exposure to various drugs of abuse, but most notably with opioids, alcohol and nicotine. Examples of physical withdrawal signs associated with opioids and nicotine include wet dog shakes, yawns, teeth chatters, dyspnea and ptosis (Malin et al., 1992; Higgins and Sellers, 1994; Hildebrand et al., 1997). Although physical withdrawal is an important factor in continued drug use, physical signs of withdrawal may be an insufficient measure that does not capture the whole picture of the aversive motivational state of a dependent animal. Drug withdrawal can also have significant aversive cognitive and affective properties (Baker et al., 2004b; Kelley et al., 2005; Jacobsen et al., 2007). Recently, techniques have been developed to address these important effects of withdrawal in animal models. Intracranial self-stimulation (ICSS) has been used to measure the rewarding effects of abused drugs, but has also been used to assess the aversive effects of drug withdrawal. ICSS is incredibly reinforcing in rats and will maintain self-administration behaviour at the expense of eating and drinking (Olds and Milner, 1954; Milner, 1991). Changes in ICSS behaviour therefore are thought to reflect the rewarding valence of other stimuli (Markou
37
and Koob, 1993). Reductions in reward threshold are typically observed in animals administered a rewarding drug, but increases in reward threshold are observed in animals undergoing withdrawal, i.e., they require more intense stimulation due to a decrease in brain reward function (Markou and Koob, 1991; Schulteis et al., 1995; Epping-Jordan et al., 1998). This technique is useful in determining the changes in brain reward function in dependent animals, but requires extensive training and surgical procedures that limit its use in rapidly developing animals such as adolescents. Negative affective properties of withdrawal can also become associated with environmental stimuli and as such, these CS can play an important role in maintaining drug use (Childress et al., 1994). Similar to the CPP paradigm in which rewarding stimuli elicit an approach response, aversive stimuli, including withdrawal, can elicit an avoidance response, i.e., a conditioned place aversion (CPA). In drug-dependent animals, the withdrawal state can be sufficiently aversive such that only one conditioning trial is necessary to elicit a CPA. This easily administered test may thus be ideal for assessing the negative affective properties of drug withdrawal in adolescent rodents.
Section 5.2.2. Extinction and reinstatement: an animal model of relapse Relapse to drug taking may be the most persistent problem in drug addiction and occurs well beyond the period of withdrawal (Hunt et al., 1971; Childress et al., 1999; Grimm et al., 2001). Animal models have been developed to address the behavioural and neurobiological underpinnings of relapse behaviour and are mainly derived from the original reinstatement model of relapse (de Wit and Stewart, 1981, 1983). In the reinstatement model, animals are initially trained to self-administer a drug, and upon stable responding, are then subject to an extinction procedure during which the drug is no longer 38
available. Extinction of responding is an important measure to study because it reflects persistence of drug seeking behaviour in the absence of the drug and can provide a measure of the reinforcing effects of a drug (Bozarth, 1990). Following extinction of responding (designated as a specific criterion of non-responding, e.g., 0.05). Intake declined in both age groups across the FR1 sessions (F(5,146) = 4.31, p < 0.001), but remained stable during the FR2 sessions (p > 0.05). When the reinforcement schedule was increased to FR5, adolescent and adult rats earned a similar number of saccharin reinforcements (p > 0.05). The number of saccharin reinforcements earned increased across sessions in adolescent, but not adult rats (F(5,130) = 3.40, p < 0.01). Examination of saccharin intake based on body weight indicated that adolescents consumed more saccharin compared to adults (F(1,26) = 30.66, p < 0.001). Concentration-response. During the concentration-response determination, adolescent and adult rats earned a similar number of saccharin reinforcements (p > 0.05) although intake was greater in the former group (F(1,26) = 13.85, p < 0.001; Table 4). A significant main effect of saccharin concentration emerged (F(3,78) = 34.21, p < 0.001), indicating that as saccharin concentration increased, reinforcements earned increased, and this effect was independent of age (p > 0.05). The number of reinforcements earned was similar at the two lower concentrations, i.e., 0.025 and 0.05%, and increased significantly at the 0.1% and 0.2% concentrations. PR responding. Figure 10a presents mean (± SEM) number of saccharin reinforcements earned and median BP achieved during the three PR sessions. Rats that initiated saccharin self-administration as adolescents and adults earned a similar number of saccharin reinforcements (p > 0.05) and both age groups demonstrated a significant decline in reinforcements earned over
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Table 4. Saccharin self-administration in adolescent and adult rats Reinforcement schedule FR1
FR2
Concentration-response FR5
0.025%
0.05%
0.10%
0.20%
Adolescents 23.54* (3.00) 17.86* (2.630) 12.75 (1.83)
15.89 (1.57)
14.69 (1.81)
27.31 (3.42)
37.83 (6.64)
Adults
21.62 (4.11)
46.02 (8.74)
Saccharin reinforcements 58.88 (8.31)
32.45 (4.88)
10.30 (1.72)
15.15 (1.58)
10.52 (1.91)
Adolescents 21.10 (2.93)
12.68 (1.89)
7.93* (1.15)
7.57* (0.99)
13.15* (2.14) 15.23* (2.29) 19.05* (3.01)
Adults
8.66 (1.32)
2.76 (0.46)
4.11 (0.60)
ml/kg consumed 15.47 (2.23)
*Significantly different from adults, p < .05 (Tukey’s HSD post hoc test); n = 14 per age
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5.92 (1.22)
5.87 (1.23)
12.41 (2.49)
60
160
50
Adolescent-onset Adults
40
120
30
80
20 40 10 0
0 1
2
Last completed ratio (Median)
Saccharin reinforcements (2 h)
a. Experiment 3
3
PR session
160
60 50 40
Adolescents Adults
120 80
30 20
40 10 0
Last completed ratio (Median)
Saccharin reinforcements (2 h)
b. Experiment 4
0 1
2 PR session
Figure 10. Saccharin self-administration under progressive ratio conditions in adolescent and adult rats. Mean (± SEM) number of saccharin reinforcements earned during 2 hr PR sessions (bars) and median breakpoints, or last completed ratio achieved (lines) in (a) rats that initiated saccharin self-administration as adolescents (adolescent-onset) and adults in Experiment 3, n = 14 per age, (b) adolescent and adult rats in Experiment 4, n = 8 per age.
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the three PR sessions (F(2,52) = 22.23, p < 0.001). Analysis of BP also revealed no significant age difference (p > 0.70). Extinction. Figure 11 presents the mean (± SEM) number of active lever responses during the last FR5 session and the first 8 extinction sessions. Responding on the saccharin-associated lever declined significantly across extinction sessions (F(9, 227) = 23.46, p < 0.001), and this was independent of age (p > 0.05). Experiment 4: Saccharin self-administration under a PR schedule. Figure 10b presents mean (± SEM) number of saccharin reinforcements earned and median breakpoints achieved during the two PR sessions. Adolescent and adult rats earned a similar number of saccharin reinforcements and analysis of breakpoint also revealed no significant age difference (both, p > 0.05).
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Active lever presses (1 h)
250 Adolescent-onset Adult-onset
200 150 100 50 0 FR5 1
2
3
4
5
6
7
8
Extinction session
Figure 11. Extinction of saccharin seeking in rats that initiated self-administration during adolescence and adulthood. Mean ± SEM number of responses on the previously active lever during the last session at FR5 and the first 8 sessions of extinction. During this phase, lever responding resulted in the presentation of the compound light-tone stimulus previously paired with saccharin delivery and was not reinforced with saccharin; n = 14 per age.
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Discussion The current study examined three measures of nicotine-taking behavior in rats that were trained to self-administer nicotine during adolescence or adulthood. First, we used a drug self-administration procedure under fixed-ratio and progressive ratio schedules that has been employed to assess the reinforcing effects of nicotine and other drugs (Richardson and Roberts, 1996; Picciotto and Corrigall, 2002; Wise, 2004). We then used a reinstatement procedure to assess relapse to drug seeking induced by acute re-exposure to the self-administered drug or other stimuli following extinction of nicotine-maintained responding (Stewart, 2000; Le and Shaham, 2002; Shaham et al., 2003; Weiss, 2005). Using these tests we did not find evidence for increased vulnerability to nicotine-taking behavior in adolescent rats. On the contrary, on several measures (PR, FR5 and extinction responding), lever responding of the rats trained for nicotine self-administration during adolescence was significantly lower than the rats that were trained to self-administer the drug during adulthood. The present data from established rat models of drug selfadministration and drug relapse suggest that age-dependent psychosocial differences, rather than biological differences in the rewarding effects of nicotine, likely account for the high rates of initiation of cigarette smoking in adolescents. Nicotine self-administration in adolescent and adult rats We examined potential differences in the reinforcing effects of nicotine between adolescent and adult rats in the intravenous self-administration procedure. Under conditions of low response cost (FR1 or FR2 schedules), adolescent and adult rats self-administered nicotine at similar rates, indicating that nicotine acts as a positive reinforcer in both age groups. In contrast, at higher response costs (FR5 or PR schedules), nicotine self121
administration was higher in adult than in adolescent rats. This age difference appears specific to nicotine, since it did not occur with a non-drug reinforcer, saccharin. These present findings with the FR1 and FR2 reinforcement schedules are consistent with the study by Belluzzi and colleagues (2005) in which no age differences for nicotine self-administration were observed under the FR1 reinforcement schedule. Our results are also partly consistent with the study by Levin and colleagues (2003), in which adolescent and adult female rats earned a similar number of nicotine infusions during the early phase of training, when the younger rats were in late adolescence (P43-46). Adult rats showed a dose-dependent decrease in nicotine self-administration, a finding consistent with previous reports (Corrigall and Coen, 1989; Shoaib et al., 1997; Watkins et al., 1999; Le et al., 2006). In contrast, increasing the nicotine dose had minimal effect on responding in adolescent rats. The flattened dose-response curve for the adolescents suggests that, compared to adults, they may be insensitive to changing doses of nicotine, or that the nicotine dose-response curve is shifted in these younger animals. The upward shift in the dose-response curve for the adult rats may reflect increased reinforcing effects of nicotine in the adult rats (Piazza et al., 2000). Alternatively, the increase in infusions earned by adults at the lower nicotine doses may result from reduced nicotine reinforcement, causing a rightward shift in the dose-response curve. This is unlikely, however, since the results from the PR testing are inconsistent with the idea that nicotine is less reinforcing in adults than in adolescents. One explanation of the findings with the FR5 and PR reinforcement schedules is that adolescents might be less capable of performing under higher response costs due to the greater physical effort required. To address this, experiments using saccharin as the
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reinforcer were conducted. Under low response requirements, adult rats earned more saccharin reinforcements compared to adolescents. This is likely attributable to the smaller body size, and thus, consummatory limitations of the adolescent rats. Saccharin intake (ml/kg), however, was similar across age groups. Upon increasing the schedule to FR5, both adolescents and adults lever pressed similarly for saccharin and earned a similar number of saccharin reinforcements in Experiments 3 and 4. These results suggest that our findings with nicotine are not due to age-dependent differences in performance. This possibility however, cannot be ruled completely out since both age groups exhibited decreases in the number of saccharin reinforcers earned when the reinforcement schedule was increased and PR responding for saccharin was lower than that for nicotine. The higher nicotine intake in adult rats may be attributable to a greater nicotineinduced enhancement of the rewarding effects of the compound (light+tone) cue associated with nicotine delivery (Caggiula et al., 2001). While not specifically tested, the similarity in nicotine priming-induced reinstatement across age argues against this possibility (see below). The finding that nicotine may be less reinforcing in adolescent than in adult rats, as measured in the self-administration procedure is surprising in light of previous studies using CPP and CTA procedures. The results of these studies suggest that nicotine is more rewarding and less aversive in adolescents compared to adults (Vastola et al., 2002; Belluzzi et al., 2004; Torrella et al., 2004; Wilmouth and Spear, 2004; Shram et al., 2006). There are several possible reasons for this potential discrepancy. In the CPP and CTA studies, nicotine is injected non-contingently via the subcutaneous route, while in the selfadministration studies, nicotine is earned contingently via the intravenous route. The
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intravenous injections would result in a more rapid increase in brain levels of nicotine than the subcutaneous route and it has previously been shown that the more rapidly nicotine or other drugs reach the brain the greater their abuse liability (Shoaib, 1996). There is also evidence in studies using adult rats that contingent and non-contingent drug exposure have different effects on brain and behavior (Wilson et al., 1994; Dworkin et al., 1995; Jacobs et al., 2003). In addition, it is not surprising that different results are obtained in a classical conditioning CPP procedure and an operant self-administration procedure; there is evidence in the literature for both similarities and differences in the anatomical substrates of the reinforcing effects of drugs, as measured in the two procedures (Bardo and Bevins, 2000). Extinction and reinstatement of nicotine seeking in adolescent and adult-onset rats Early onset of tobacco use is associated with a reduced probability of quitting and higher rates of relapse (Breslau and Peterson, 1996; Chen and Millar, 1998; Cui et al., 2006). In the current study, we assessed relapse to nicotine seeking, as measured in extinction and reinstatement tests, in rats that initiated nicotine self-administration as adolescents (adolescent-onset) or adults (adult-onset). Adult-onset rats demonstrated greater resistance to extinction under saline substitution conditions when compared with adolescent-onset rats. This observation is consistent with our finding of a greater reinforcing efficacy of nicotine in adult rats under the PR schedule and extends the findings by Donny et al. (2004) and Roth and Carroll (2004) relating rate of acquisition of drug self-administration and BP. The greater resistance to extinction also potentially suggests that the compound cue associated with nicotine delivery acquired greater conditioned reinforcing effects in the adult rats than in
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the adolescent rats. However, the greater number of nicotine-cue pairings in the adult rats may have also contributed to this effect. Unlike extinction responding, no age differences were observed in the effect of nicotine priming on reinstatement of drug seeking. For both age groups, nicotine priming injections reliably reinstated nicotine seeking, an observation consistent with previous reports (Shaham et al., 1997; Le et al., 2006). The mechanisms underlying nicotine-induced reinstatement are unknown. Stewart and colleagues (1984) suggested that drug priming restores the incentive value of extinguished drug-associated cues, resulting in resumption of drug seeking. Alternatively, nicotine priming may enhance responding for the compound cue, which can have intrinsic reinforcing properties of its own (Caggiula et al., 2001; Olausson et al., 2004; Chaudhri et al., 2005), rather than increasing nicotine seeking per se. The former interpretation may be more likely because the effect of nicotine priming injections on reinstatement of lever responding is to some degree stimulus specific. While there is evidence that nicotine can reinstate alcohol seeking (Le et al., 2003) and cocaine seeking in alcohol-preferring P rats (Le et al., 2006), it does not reinstate cocaine seeking in alcohol non-preferring (NP) rats (Le et al., 2006) or other rat strains (Wise et al., 1990; Schenk and Partridge, 1999). Also, nicotine priming injections do not reinstate food seeking (Shaham et al., 1997) and, surprisingly, attenuate reinstatement of methamphetamine seeking (Hiranita et al., 2004). Our data suggest that age of onset of nicotine self-administration does not influence nicotine priming-induced reinstatement of nicotine seeking during adulthood. It remains to be seen if cue or stress-induced reinstatement of nicotine seeking is differentially affected by age at onset of nicotine self-administration. In addition, it would be interesting to test
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extinction and reinstatement during the adolescent period; the ability to investigate this possibility is limited by the brevity of the adolescent period. Concluding remarks In the present series of experiments, we did not find evidence for an enhanced vulnerability to the rewarding and relapse-provoking effects of nicotine in adolescent rats. These findings are in apparent contrast to the epidemiological literature on increased vulnerability to nicotine addiction in humans during adolescence. These findings suggest that age-dependent psychosocial and behavioral differences (Spear, 2000; Simons-Morton et al., 2001; Deakin et al., 2004; Kelley et al., 2004), rather than biological differences in the rewarding effects of nicotine, likely account for the high rates of initiation of cigarette smoking in adolescents. This is a likely conclusion because in generalizing the present findings to humans, it is important to note that the subjects in our experiments were randomly assigned to age of onset of nicotine self-administration. In contrast, in human studies, vulnerable individuals are likely to initiate smoking during adolescence and therefore, are unlikely to be represented in a sample of adult-onset smokers. Albeit surprising, our findings that adolescent rats are less willing to work for nicotine at high response costs agree with the results of a number of studies in humans. Interestingly, the adolescent age group has been shown to be the most sensitive to increases in cigarette prices (Ding, 2003) and they are also the most likely age group to seek noncommercial (and easier to obtain) sources of cigarettes (Castrucci et al., 2002). Although our findings do not indicate an enhanced vulnerability to the reinforcing effects of nicotine during adolescence, repeated exposure to nicotine during this vulnerable stage
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has been shown to produce long-term neurobehavioural consequences (Trauth et al., 1999; Trauth et al., 2001; Adriani et al., 2003).
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Significance of chapter This was the first study to compare the direct reinforcing efficacy of nicotine in adolescent and adult rats using higher FR and PR reinforcement schedules in the operant intravenous self-administration paradigm. Contrary to our hypothesis, nicotine was less reinforcing in adolescent compared to adult rats under the PR schedule, but both age groups self-administered similarly under simple reinforcement schedules. While the latter suggests that adolescents and adults find nicotine rewarding, the former indicates that adults are more motivated to obtain nicotine because they are willing to work harder for it compared to adolescents. Adult rats were also more resistant to extinction compared to rats that initiated self-administration during adolescence, providing further evidence that nicotine may be more reinforcing in adults. This was also the first study to investigate the influence of age at initiation upon nicotine priming-induced reinstatement. Both groups, independent of age at initiation, were equally susceptible to nicotine priming-induced reinstatement of nicotine seeking. The findings under operant self-administration conditions did not demonstrate an enhanced susceptibility to the reinforcing effects of nicotine in adolescence. Although nicotine is rewarding in adolescent rats, they are less willing to work for it when response costs are high. This finding may have direct positive implications in that it suggests that increasing the cost of cigarettes may be one of the most effective methods of reducing smoking in adolescents.
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CHAPTER 5: AGE DIFFERENCES IN THE SPONTANEOUS ACQUISITION OF NICOTINE SELF-ADMINISTRATION IN MALE WISTAR AND LONG EVANS RATS
M.J. Shram, Z. Li and A.D. Lê Based on Psychopharmacology, accepted. All experiments, data analysis and manuscript writing were conducted by M.J. Shram. Z. Li assisted in completing the experimental work. Study design was a collaborative effort between A.D. Lê and M.J. Shram. A.D. Lê was involved in reviewing the manuscript prior to submission.
Reprinted from: Shram et al. (2007) Age differences in the spontaneous acquisition of nicotine self-administration in male Wistar and Long Evans rats. Psychopharmacology, accepted. With permission from Springer-Verlag. © 2007 Springer-Verlag. All rights reserved. 129
Abstract Epidemiological evidence suggests that adolescents may exhibit a unique susceptibility to the motivational effects of nicotine compared to adults. In contrast to the hypothesis of an enhanced vulnerability to nicotine during adolescence, we have observed that nicotine is less reinforcing in adolescent compared to adult rats using a progressive ratio reinforcement schedule in an operant self-administration procedure, although prior operant conditioning experience may have masked differences in initial sensitivity to nicotine. This study examined the spontaneous acquisition of nicotine self-administration in adolescent (postnatal day (PD) 31) and adult (PD87) male Wistar and Long Evans rats. Rats selfadministered nicotine (0.015 or 0.03 mg/kg/infusion, i.v.) during 2-h operant conditioning sessions under fixed-ratio-1 (FR1) and FR3 reinforcement schedules for six sessions each. A subset of rats (adolescents: PD42, adults: PD98) underwent extinction of responding and nicotine priming-induced reinstatement (0.15 mg/kg, s.c.). In a separate group of rats, saccharin self-administration (0.1 ml of 0.2% w/v) was tested to determine the specificity of our findings with nicotine. A greater proportion of adult compared to adolescent rats acquired self-administration of 0.015 mg/kg/infusion nicotine, but both age groups readily acquired self-administration 0.03 mg/kg/infusion nicotine and saccharin. Age differences in extinction of responding for nicotine or saccharin depended upon strain, but priminginduced reinstatement was similar across age and strain. The current findings are consistent with those obtained under a more demanding progressive ratio reinforcement schedule and suggest that adolescents, compared to adults, may not be as sensitive to the reinforcing effects of nicotine.
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Introduction Eighty percent of adult smokers report starting to smoke prior to age 18 (SAMHSA, 2003) and initiation rarely occurs beyond this age (Department of Health and Human Services, 1994). Such early onset of tobacco use is associated with a more rapid progression to dependence (Colby et al., 2000), a reduced probability of quitting (Breslau and Peterson, 1996; Chen and Millar, 1998) and an increased likelihood of developing an alcohol or substance use disorder compared to later onset (Grant and Dawson, 1998; Hanna et al., 2001; Agrawal et al., 2006). Such epidemiological evidence indicates that adolescence is a uniquely vulnerable period in the initiation of smoking. Adolescents exhibit a number of behavioural traits that might contribute to an enhanced vulnerability to drug taking, including elevated risk taking, novelty seeking and impulsivity (Arnett, 1992; Zuckerman, 1994; Chambers et al., 2003). Adolescent rodents and nonhuman primates also show similar behavioural and neurobiological characteristics; the use of these models has been important in identifying factors contributing to adolescent drug use (e.g., impulsivity, novelty seeking, Spear, 2000; Laviola et al., 2003; Barr et al., 2004). Recent evidence indicates that adolescent rats (postnatal days (PD) 28-42) may be more sensitive to the rewarding effects of nicotine as measured in the conditioned place preference (CPP, Vastola et al., 2002; CPP, Belluzzi et al., 2004; Shram et al., 2006) and self-administration paradigms (Adriani et al., 2002; Levin et al., 2003; Chen et al., 2007; Levin et al., 2007). However, not all have reported enhanced nicotine self-administration during adolescence (Belluzzi et al., 2005; Shram et al., 2007). We recently demonstrated that nicotine self-administration is similar in adolescent and adult rats under simple fixed
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ratio (FR) reinforcement schedules, but that nicotine is less reinforcing in adolescents when tested in a more demanding progressive ratio reinforcement schedule (Shram et al., 2007). A number of factors may have contributed to our findings, including prior operant training and habituation to the chambers that would mask age differences in exploratory behaviour potentially important in acquisition of self-administration (Adriani et al., 1998; Macri et al., 2002; Stansfield and Kirstein, 2006). Assessment was also restricted to a single maintenance dose of nicotine. Spontaneous acquisition of self-administration is an important determinant of the reinforcing strength of a drug (Deminiere et al., 1989; Donny et al., 2004) and has been used to test the influence of individual differences in behaviour, e.g., novelty seeking, on the initiation of drug taking (Piazza et al., 1989; Piazza et al., 1991; Poulos et al., 1995; Suto et al., 2001). Under these conditions, higher rates of acquisition presumably reflect an increased vulnerability to the reinforcing effects of a drug. For this reason, we examined the spontaneous acquisition of nicotine self-administration in untrained adolescent and adult rats. To evaluate developmental differences in sensitivity to nicotine, we investigated acquisition in Long Evans (LE) and Wistar rats using two infusion doses located on the ascending portion of the dose-response curve generated from studies employing adult male rats (Corrigall and Coen, 1989; Donny et al., 1995). These two strains readily selfadminister nicotine (Corrigall and Coen, 1989; Chiamulera et al., 1996; Shoaib et al., 1997; Watkins et al., 1999) and have previously been employed in studies examining age differences in drug responsivity (Cruz et al., 2005; Shram et al., 2006; 2007; Wiley et al., 2007). We also tested extinction and priming-induced reinstatement of nicotine seeking, a validated animal model of relapse (Shaham et al., 2003; Epstein et al., 2006), during
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adolescence. Finally, we examined age differences in the spontaneous acquisition of saccharin self-administration to determine the specificity of our findings with nicotine.
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Materials and Methods Animals Fifty-three day old male LE (n = 30) and Wistar (n = 30) rats and pregnant LE (n = 9) and Wistar (n = 9) dams were purchased from Charles River Laboratories (Quebec, Canada). Adults were group housed (n=4 per cage), and dams were singly housed in Plexiglas cages (51 x 41x 20 cm). Following birth, pups remained undisturbed with their mother. Sixty-six male pups (n = 33 each LE and Wistar) were weaned and housed by litter on PD20. Littermates were assigned to different nicotine infusion dose groups to avoid the potential confound of litter effects. Rats were maintained on a 12/12h light/dark cycle (lights on at 1900 hours) in a humidity and temperature-regulated vivarium. Water and Purina rat chow were available ad libitum except during the self-administration sessions. Apparatus Nicotine self-administration occurred in eight operant conditioning chambers operated by a Med Associates interface system (St. Albans VT). Each chamber was equipped with two levers located 2.5 cm above a grid floor. Pressing the active lever activated the infusion pump (PHM-100VS, Med Associates) that delivered the nicotine solutions via Tygon tubing protected by a metal spring. A white cue light and a tone generator (2,900 Hz) were turned on when the active lever was pressed. Pressing the inactive lever was recorded, but had no programmed consequences. A houselight on the opposite side of the chamber signaled session onset. Saccharin self-administration occurred in eight similarly equipped operant conditioning chambers (Med Associates), with the exception of a liquid drop receptacle located between the active and inactive levers. Responding on the active lever resulted in 134
the activation of the visual and auditory stimuli and a syringe pump (PHM-100 Med Associates) equipped with a 60 ml syringe, which delivered 0.1 ml saccharin. Surgery Juvenile (PD26-27) and adult rats (PD81-83) were prepared with catheters implanted into the right jugular vein as previously described (Corrigall and Coen, 1989; Shram et al., 2007). Surgical anaesthesia was induced by administration of ketamine (75 mg/kg, Vetoquinol, Lavaltrie, QC, Canada) and xylazine (10 mg/kg, Bayer, Toronto, ON, Canada) delivered in a volume of 3 ml/kg, i.p., for adolescents and 2 ml/kg, i.p., for adults. Rats were individually housed following surgery to facilitate recovery (4-6 days) and to protect the catheters. Catheters were flushed daily with 0.1 ml of a sterile heparin-saline solution (50 U/ml) to maintain patency. Drugs Nicotine solutions (Sigma-Aldrich, Oakville, ON, Canada) were prepared daily using sterile saline, and pH was adjusted to 6.8-7.2. The unit doses for nicotine selfadministration were 0.015 and 0.03 mg/kg/infusion, expressed as base (Corrigall and Coen, 1989; Shoaib and Stolerman, 1999; Shram et al., 2007). During the tests for reinstatement, nicotine (0.15 mg/kg) was administered subcutaneously in a volume of 1 ml/kg (Shaham et al., 1997; Le et al., 2006). Catheter patency was tested at the end of the study using the rapid acting anaesthetic, sodium methohexital (0.025 mg/kg (adolescent) or 0.05 mg/kg (adult), i.v., 10 mg/ml).
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Procedures Experiment 1: Spontaneous acquisition, extinction and reinstatement of nicotine selfadministration. Adolescent (PD31, n = 20 each LE and Wistar) and adult (PD87, n = 20 each LE and Wistar) rats initiated self-administration of nicotine (0.015 or 0.03 mg/kg/infusion, i.v.) under a FR1 reinforcement schedule for six daily 2-h sessions. Timeout following each nicotine infusion was 20 sec. Rats were then placed under a FR3 reinforcement schedule for an additional six sessions. To meet acquisition criteria, rats had to demonstrate 1) a preference for the active over the inactive lever (2:1), 2) a progressive increase in active lever responding across sessions and 3) a minimum of 10 active lever presses (including time out lever presses) in the majority of sessions (> 7 days). These criteria are similar to those reported previously (Shoaib and Stolerman, 1999; Chen et al., 2007). Selfadministration sessions occurred daily for a total of twelve consecutive days. A subset of rats that met acquisition criteria at 0.03 mg/kg/infusion (n = 7 adolescents (PD42) and n = 8 adults (PD98)) was included in the extinction procedure that began the day following the last self-administration session. Extinction conditions were the same as the nicotine self-administration sessions with the exception that pressing on the active lever resulted in the infusion of saline instead of nicotine. Nicotine-associated cues (light+tone) were provided and contingent upon lever pressing behaviour. Each rat had four 1 hr extinction sessions per day for two consecutive days (two sessions each in the morning and afternoon). On the third day, rats underwent extinction until criterion was met (< 15 presses on the nicotine-associated lever for two consecutive sessions) prior to testing for reinstatement. A vehicle priming test preceded the nicotine priming (0.15 mg/kg, s.c.)
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reinstatement test. Vehicle or nicotine was administered 30 min prior to testing, and reinstatement tests were 1 hr in duration; no nicotine was available during the tests for reinstatement. Experiment 2: Spontaneous acquisition, extinction and reinstatement of saccharin selfadministration. Procedures were similar to those used with nicotine, except that nicotine was substituted with orally administered saccharin (0.1 ml of 0.2% saccharin dissolved in water) as the reinforcer. Adolescent and adult rats previously trained on the operant response show similar self-administration of this saccharin concentration (Shram et al., 2007). Consumption of the saccharin solution was verified at the end of each selfadministration session by measuring the amount of saccharin remaining in the liquid drop receptacle. The reinstatement test included a saccharin prime (0.1 ml) that was placed in the drop receptacle immediately before the test. Statistical analysis Fisher’s exact test was used to compare the proportion of adolescent and adult rats that acquired nicotine or saccharin self-administration. Lever responding (active and inactive) and nicotine infusions earned (or saccharin intake) during the self-administration sessions were analyzed using repeated measures analyses of variance (ANOVAs) for each reinforcement schedule separately with the following design: Age (2) x Strain (2) x Dose (2) x Session (6). All rats with patent catheters (acquired and not acquired) were included in the analyses of nicotine self-administration. In the saccharin study, intake was expressed as ml/kg consumed to account for the large weight differences between age groups (Mean ± SEM: adolescents: 130.8 ± 3.3 g; adults: 467.2 ±18.3 g). Rate of acquisition was
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calculated as the slope of the acquisition curve for each rat obtained from the number of active lever presses over the six FR1 sessions, and subsequently analyzed by ANOVA. Extinction and reinstatement of responding on the nicotine- or saccharin-associated lever were analyzed by repeated measures ANOVA (Extinction: Age x Session and reinstatement: Age x Priming dose). Significance was set at α = 0.05. Tukey’s HSD was employed for all post hoc tests where appropriate. Statistical analyses were performed using SPSS version 13.0.
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Results Spontaneous acquisition, extinction and reinstatement of nicotine self-administration. Independent of strain, a greater proportion of adult rats acquired self-administration of 0.015 mg/kg/infusion nicotine compared to adolescent rats (Table 5, Fisher’s exact test, p < 0.05). No age differences were observed at the higher (0.03 mg/kg/infusion) dose (p > 0.05). Overall, there were no strain differences in the proportion of rats meeting acquisition criteria (p > 0.05), but fewer rats acquired self-administration of the 0.015 mg/kg/infusion nicotine compared to rats self-administering 0.03 mg/kg//infusion (p < 0.001). The four-way interaction (Session x Strain x Age x Dose) was not significant for lever responding or nicotine infusions earned (both, p > 0.05) however, repeated measures ANOVA revealed a number of significant interactions, most notably those of Session x Age x Strain for lever responding (F(5,345) = 2.20, p < 0.05) and nicotine infusions earned (F(5,350) = 3.00, p < 0.05), and a Session x Lever x Age (F(5,345) = 3.43, p < 0.001) for lever responding under the FR1 schedule. Analysis of lever responding also revealed significant interactions of Session x Age (F(5,345) = 2.70, p < 0.05), Session x Strain (F(5,345) = 4.51, p < 0.001), Session x Dose (F(5,345) = 2.68, p < 0.05), Session x Lever (F(5,345) = 4.90, p < 0.001), Lever x Age (F(1,69) = 12.36, p < 0.001), Lever x Strain (F(1,69) = 5.83, p < 0.05), as well as main effects of Session (F(5,345) = 6.05, p < 0.001) and Lever (F(1,69) = 90.23, p < 0.001). Additionally, the Strain x Age (F(1,70) = 3.97, p < 0.05), Session x Strain (F(5,350) = 4.16, p < 0.001), Session x Age (F)5,350) = 4.52, p < 0.001) and Session x Dose (F(5,350) = 4.77, p < 0.001) interactions, and main effects of
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Table 5. Proportion of rats spontaneously acquiring self-administration 0.015 mg/kg/infusion nicotine
0.03 mg/kg/infusion nicotine
Saccharin (0.2 %)
Adolescents
Adults
Adolescents
Adults
Adolescents
Adults
Long Evans
3/10
7/10
7/10
10/10
9/13
8/10
Wistar
1/9
4/10
7/10
7/10
11/13
7/10
Total
4/19
11/20*
14/20**
17/20**
20/26
15/20
*Significantly different from adolescents in 0.015 mg/kg/infusion condition, p < 0.05 **Significantly different from rats in 0.015 mg/kg/infusion condition, p < 0.001
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Session (F(5,350) = 8.31, p < 0.001) and Dose (F(1,70) = 4.28, p < 0.05) were significant for nicotine infusions earned under the FR1 reinforcement schedule. Thus, due to significant differences across strain, and for simplicity in describing our findings in terms of potential age differences in acquisition, extinction and reinstatement, results from each strain are presented separately, and where appropriate, by nicotine dose. Long Evans Analysis of lever responding under the FR1 schedule revealed a significant Session x Age x Dose interaction (F(5,175) = 2.40, p < 0.05). Considering this, acquisition was analyzed at each dose separately for the Long Evans strain. Acquisition at 0.015 mg/kg/infusion. Analysis of the slope of the acquisition curve revealed that adults acquired self-administration more rapidly compared to adolescents (F(1,18) = 9.26, p < 0.01). Lever responding increased across FR1 sessions (Fig. 12a, Session: F(5,90) = 2.46, p < 0.05) and active lever responding exceeded that of inactive lever responding (Lever: F(1,18) = 27.33, p < 0.001). Simple effect analysis of significant Session x Age (F(5,90) = 3.07, p < 0.05) and Lever x Age (F(1,18) = 9.64, p < 0.05) interactions demonstrated that both age groups discriminated between the two levers (adolescents: F(1,9) = 5.17, p < 0.05; adults: F(1,9) = 22.19, p < 0.001), but active lever responding increased across FR1 sessions in adult rats only (Session: F(5,40) = 4.77, p < 0.01). Adolescent and adult LE rats maintained their preference for the active lever under the FR3 schedule (Lever: F(1,18) = 20.05, p < 0.001). This effect depended upon age (Lever x Age: F(1,18) = 7.61, p < 0.05), with adults exhibiting greater responding on the active (Age: F(1,18) = 5.38, p < 0.05), but not inactive (p > 0.05), lever compared to adolescents. 141
Long Evans a Lever presses (2 h)
100
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Long Evans
Infusions earned (2h)
a 40 35 30 25 20 15 10 5 0
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0.015 mg/kg FR1*
FR3* Adolescents Adults
40 35 30 25 20 15 10 5 0
0.03 mg/kg FR1
FR3
1 2 3 4 5 6 7 8 9 10 11 12 Session
1 2 3 4 5 6 7 8 9 10 11 12 Session
Wistar
Infusions earned (2h)
c 40 35 30 25 20 15 10 5 0
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0.015 mg/kg FR1
FR3
1 2 3 4 5 6 7 8 9 10 11 12 Session
40 35 30 25 20 15 10 5 0
0.03 mg/kg FR1
FR3
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Figure 13. Nicotine infusions earned by adolescent and adult male rats spontaneously acquiring nicotine self-administration. Data are presented as mean (+SEM) nicotine infusions earned by LE (a,b) and Wistar (c,d) rats self-administering 0.015 or 0.03 mg/kg/infusion nicotine during daily 2-h operant sessions under FR1 and FR3 reinforcement schedules (n = 9-10 per age, each strain). *Adult LE rats earned significantly more nicotine infusions compared to LE adolescent rats selfadministering 0.015 mg/kg/infusion nicotine, p < 0.05.
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Consistent with lever responding, adults earned significantly more nicotine infusions compared to adolescents under both FR1 (F(1,18) = 5.38, p < 0.05) and FR3 (F(1,18) = 10.47, p < 0.01) schedules (Fig. 13a). Under FR1, analysis of a significant Session x Age (F(5,90) = 4.56, p < 0.01) interaction revealed that adults demonstrated session-dependent increases in the number of infusions earned (Session: F(5,45) = 4.41, p < 0.01) whereas nicotine intake by adolescents remained stable across sessions (p > 0.05). Acquisition at 0.03 mg/kg/infusion. Examination of acquisition slopes demonstrated that adolescent and adult LE rats acquired self-administration at a similar rate (p > 0.05). Both age groups discriminated between the active and inactive levers under the FR1 schedule (Fig. 12b, Lever: F(1,17) = 51.64, p < 0.001), with active lever responding increasing across sessions (F(5,85) = 8.27, p < 0.001). A significant Lever x Age interaction (F(1,17) = 5.68, p < 0.05) indicated that adult LE rats responded more on the active lever compared to adolescent LE rats (Age: F(1,18) = 5.38, p < 0.05), but inactive lever responding was similar across age (p > 0.05). Under FR3, a significant Session x Lever interaction (F(5,85) = 5.32, p < 0.001) indicated that, independent of age, responding on the active lever increased across sessions (Session: F(5,85) = 6.76, p < 0.001), but not on the inactive lever (p > 0.05). Adolescent and adult LE rats earned a similar number of nicotine infusions (Fig. 13b, p > 0.05), and both age groups exhibited session-dependent increases in number of nicotine infusions earned under both the FR1 (Session: F(5,85) = 8.27, p < 0.001) and FR3 (Session: F(5,85) = 6.76, p < 0.001) schedules. Extinction and reinstatement of nicotine seeking. Vehicle substitution resulted in a sessiondependent decrease in responding on the nicotine-associated lever in both adolescent and
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adult LE rats (Fig. 14a, Session: F(9,117) = 13.88, p < 0.001). A Session x Age interaction (F(9,117) = 2.30, p < 0.05) indicated that adults responded more on the nicotine-associated lever compared to adolescents during the first session of Extinction day 3 (Tukey’s HSD, p < 0.05). Nicotine priming reinstated lever pressing on the nicotineassociated lever (Fig. 14b, F(1,13) = 6.64, p < 0.05) and this was independent of age (p > 0.05). Wistar Acquisition. Analyses of lever responding (Fig. 12c, 12d) and nicotine infusions earned (Fig. 13c, 13d) did not reveal significant Age x Dose interactions for the Wistar strain thus, results from both infusion dose groups were analyzed together. Rate of acquisition was similar across age (p > 0.05). Analysis of lever responding at the FR1 schedule revealed significant Session x Age (F(5,170) = 2.94, p < 0.05) and Lever x Dose interactions (F(1,34) = 5.14, p < 0.05) and main effects of Lever (F(1,34) = 24.56, p < 0.001) and Session (F(5,170) = 3.97, p < 0.01). Simple effect analysis showed that Wistar rats responded preferentially on the active lever (Lever: F(1,90) = 37.52, p 0.05) in the 0.015 mg/kg/infusion condition. Analysis of the Session x Age interaction demonstrated that adolescent Wistar rats maintained stable lever responding across sessions (p > 0.05), whereas adult Wistar rats initially showed a progressive increase across the FR1 sessions (F(5,90) = 5.52, p < 0.001). Under the FR3 schedule, a significant Lever x Dose interaction (F(1,35) = 9.28, p < 0.01) indicated that active lever responding was significantly greater by Wistar rats in the
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Extinction
Priming-induced reinstate ment
Long Evans a
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Lever presses on nicotine-associated lever
EXT1
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50 40
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Vehicle Nicotine (0.15 mg/kg, s.c.)
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Figure 14. Extinction and priming-induced reinstatement of nicotine seeking in adolescent and adult male LE and Wistar rats previously self-administering 0.03 mg/kg/infusion nicotine. Data are presented as mean (+SEM) presses on the nicotine-associated lever under saline substitution conditions (n = 7-8 per age, each strain). Extinction occurred using a modified within-between session procedure during which rats had 4 daily 1-h operant sessions over two consecutive days (a,c). On the third day, rats underwent repeated extinction sessions until responding ceased and were subsequently primed with vehicle and then nicotine (0.15 mg/kg, s.c.) 30 min prior to the 1-h reinstatement sessions (b,d). *Responding on the nicotine-associated lever was greater in adult compared to adolescent Wistar rats, p < 0.05. †Priming with nicotine, but not vehicle, reinstated lever responding in both adolescent and adult rats, p < 0.05.
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0.03 mg/kg/infusion condition compared to those in the 0.015 mg/kg/infusion condition (F(1,35) = 9.31, p < 0.05); no differences in inactive lever responding were evident across Dose condition (p > 0.05). The main effects of Session (F(5,175) = 3.17, p < 0.01), Lever (F(1,34) = 64.42, p < 0.001) and Dose (F(1,35) = 8.51, p < 0.01) were also significant. A significant Session x Dose interaction (F(5,170) = 2.76, p < 0.05) indicated that Wistar rats self-administering 0.015 mg/kg/infusion showed a session-dependent decline in the number of infusions earned (Session: F(5,85) = 2.41, p < 0.05), whereas daily nicotine intake by Wistar rats self-administering 0.03 mg/kg/infusion remained stable (p > 0.05) under the FR1 schedule. Main effects of Dose under the FR1 (F(1,34) = 7.38, p < 0.05) and FR3 (F(1,35) = 12.35, p < 0.01) schedules showed that Wistar rats in the 0.03 mg/kg/infusion condition earned significantly more nicotine infusions compared to Wistar rats self-administering 0.015 mg/kg/infusion nicotine. Extinction and reinstatement of nicotine seeking. Vehicle substitution resulted in a session-dependent decrease in responding (Fig. 14c, F(9,108) = 18.10, p < 0.001) that interacted with age (Session x Age: F(9,108) = 3.10, p < 0.01). Adults exhibited greater persistence in responding on the nicotine-associated lever compared to adolescents during the first 1 hr session of the first two extinction days (Tukey’s HSD, p < 0.05). Nicotine priming reinstated lever pressing on the nicotine-associated lever in both adolescent and adult Wistar rats (Fig. 14d, F(1,12) = 7.29, p < 0.05). Spontaneous acquisition, extinction and reinstatement of saccharin self-administration. Adolescent and adult rats of both strains acquired saccharin self-administration similarly (Table 1, Fisher’s exact test, p > 0.05). No significant strain differences in the proportion of rats meeting acquisition criteria were observed (p > 0.05). 147
Long Evans Acquisition. Both age groups exhibited a similar rate of acquisition (p > 0.05). There was an increase in active, but not inactive lever responding across FR1 sessions (Fig. 15a, Session x Lever: F(5,100) = 3.181, p = 0.01), with both age groups demonstrating a clear preference for the active lever (Lever: F(1,20) = 38.77, p < 0.001). This interacted with age however (Lever x Age: F(1,20) = 11.873, p < 0.01), since adults pressed significantly more on the active lever (Age: (F(1,20) = 8.43, p < 0.05). Under the FR3 schedule, there were session-dependent increases in active (Session: F(5,95) = 5.36, p < 0.001), but not inactive (p > 0.05) lever responding that was similar in both adolescent and adult rats. Saccharin intake was similar across age (Fig. 15c, p > 0.05) and stable across FR1 sessions (p > 0.05). Intake by both age groups increased during the FR3 sessions (Session: F(5,95) = 3.51, p < 0.01). Extinction and reinstatement of saccharin seeking. Responding on the saccharinassociated lever declined across extinction sessions (F(9,117) = 15.24, p < 0.001), but was independent of age (Fig. 16a, p > 0.05). Priming with saccharin increased responding on the saccharin-associated lever, but this did not reach statistical significance (Fig. 16b, p = 0.087). Wistar Acquisition. Adolescent and adult Wistar rats acquired self-administration at a similar rate (p > 0.05). Active (F(5,105) = 5.12, p < 0.001), but not inactive, lever responding increased across FR1 sessions (Fig. 15b, Session x Lever: F(5,105) = 5.67, p < 0.001). Both age groups showed a preference for the active lever (Lever: F(1,21) = 17.26, p
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Figure 15. Spontaneous acquisition of saccharin self-administration in adolescent and adult male rats. Top panels: Data are presented as mean (+SEM) active and inactive lever responses emitted during daily 2-h operant sessions by LE (a) and Wistar (b) rats self-administering 0.2% saccharin (0.1 ml) under FR1 and FR3 reinforcement schedules (n = 10-13 per age, each strain). *Active lever responding was greater in adult vs. adolescent rats, p < 0.05. Bottom panels: Data are presented as mean (+SEM) saccharin intake in milliliters per kilogram body weight by LE (c) and Wistar (d) rats. *Adolescent Wistar rats consumed significantly more saccharin compared to adult Wistar rats under the FR3 reinforcement schedule, p < 0.05.
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Figure 16. Extinction and priming-induced reinstatement of saccharin seeking in adolescent and adult male LE and Wistar rats that acquired saccharin self-administration. Data are presented as mean (+SEM) presses on the saccharin-associated lever; saccharin was not available during these sessions (n = 7-8 per age, each strain). Extinction occurred using a modified within-between session procedure during which rats had 4 daily 1-h operant sessions over two consecutive days (a,c). On the third day, rats underwent repeated extinction sessions until responding ceased and were subsequently primed with 0.1 ml saccharin that was placed into the liquid drop receptacle immediately prior to onset of the reinstatement test (b,d). *Responding on the saccharin-associated lever was greater in adolescent compared to adult Wistar rats, p < 0.05. †Priming with saccharin reinstated lever responding in both adolescent and adult Wistar rats, p < 0.05.
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< 0.001). Lever responding increased across FR3 sessions (F(5,105) = 2.68, p = 0.03), but the increase was isolated to the active lever (Session x Lever: F(5,105) = 2.58, p = 0.03) and was independent of age (p > 0.05). Under the FR1 schedule, saccharin intake by adolescent and adult Wistar rats increased across sessions (Fig. 15d, Session: F(5,105) = 5.92, p < 0.01). When the schedule increased to FR3, adolescents consumed more saccharin compared to adults (Age: F(1,21) = 6.05, p < 0.05). Extinction and reinstatement of saccharin seeking. There was a significant decline in responding on the saccharin-associated lever by adolescent and adult Wistar rats across extinction sessions (Fig. 16c, F(9,117) = 15.52, p < 0.001), but this interacted with age (Session x Age: F(9,117) = 2.56, p < 0.01). Adolescents lever pressed more than adults during the first session of the first two extinction days (p < 0.05). Saccharin priming reinstated saccharin seeking behaviour in both adolescent and adult Wistar rats (Fig. 16d, F(1,13) = 14.33, p < 0.01).
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Discussion Age differences in the spontaneous acquisition of nicotine self-administration Independent of strain, a greater proportion of adult rats spontaneously acquired selfadministration of 0.015 mg/kg/infusion nicotine compared to adolescent rats, suggesting that they were more sensitive to the direct reinforcing effects of this low infusion dose of nicotine. Furthermore, this age difference was maintained in the LE, but not Wistar rats when we analyzed lever responding and infusions earned. Interestingly, no age differences were observed in acquisition at the higher dose of nicotine (0.03 mg/kg/infusion) in either strain, indicating similar sensitivity to the reinforcing effects of this dose of nicotine under low FR reinforcement schedules. The enhanced acquisition of self-administration at 0.015 mg/kg/infusion nicotine in adult rats is consistent with our previous study indicating greater reinforcing strength of nicotine in adult compared to adolescent LE rats using a progressive ratio reinforcement schedule (Shram et al., 2007). These findings put together suggest that adolescents may be less responsive to the direct reinforcing effects of nicotine, and that higher doses may be necessary to achieve similar reinforcing strength. Reduced acquisition of 0.015 mg/kg/infusion nicotine in adolescent rats was unrelated to lower initial responding on the levers since both age groups sampled the levers similarly during the first selfadministration session (F(1,35) = 0.726, p = 0.40). Thus, the enhanced exploratory drive of adolescent rats (Adriani et al., 1998; Macri et al., 2002; Stansfield and Kirstein, 2006, but see; Douglas et al., 2003; Maldonado and Kirstein, 2005) did not enhance acquisition rates beyond that observed with adults.
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The spontaneous acquisition of nicotine self-administration by adolescent and adult LE and Wistar rats contradicts that previously observed with Sprague Dawley (Belluzzi et al., 2005) and Lewis rats (Chen et al., 2007). In the former study, adolescent and adult rats failed to acquire self-administration of 0.03 mg/kg/infusion nicotine, whereas the latter study demonstrated enhanced acquisition of this same dose in adolescent Lewis rats. Strain differences (Marks et al., 1991; Shoaib et al., 1997) may possibly explain the discrepancy in acquisition across studies, but this is unlikely since adolescent and adult rats of both strains in the current report exhibited similar acquisition of 0.03 mg/kg/infusion nicotine. A number of methodological differences may account for the disparity across studies, including timeout following nicotine infusion, type of operant response and time of testing during the light/dark cycle. Housing conditions have been shown to alter drug responsivity (Laviola et al., 2002) and self-administration (Schenk et al., 1987; but see Schenk et al., 1988), however this is unlikely to account for the observed differences since rats from all three spontaneous acquisition studies were individually housed. Nicotine self-administration appears comparable in Wistar and LE adult rats when they are initially trained on the operant response (Corrigall and Coen, 1989; Chiamulera et al., 1996; Watkins et al., 1999; Shram et al., 2007). In contrast, we observed that the number of Wistar rats (5/19) spontaneously acquiring self-administration of 0.015 mg/kg/infusion nicotine was lower compared to the LE rats (10/20). One possible factor that may contribute to this observation is a difference in sensitivity to some of nicotine’s effects. For example, nicotine may have greater anxiolytic effects in Wistar rats (Brioni et al., 1994), whereas the opposite, i.e., anxiogenesis, is reported for LE rats (Scheufele et al., 2000). Interestingly, Irvine and colleagues (2001) report that rats may self-administer
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nicotine because of its anxiogenic, rather than its anxiolytic properties. These studies might suggest that LE rats may more readily acquire nicotine self-administration due to its anxiogenic properties. The age differences observed in nicotine self-administration are unlikely to be solely related to pharmacokinetic differences, since we would expect consistent differences across a range of reinforcement schedules and doses. If metabolism of nicotine is more rapid in adolescents as previously suggested (Trauth et al., 1999), we would anticipate higher self-administration rates in the adolescent rats if they are trying to maintain an optimal level of nicotine. There is little evidence for age differences in nicotine metabolism in the rat strains tested, at least in vitro (Kyerematen et al., 1988). It is also unlikely that the adolescent rats were satiated due to higher nicotine levels since the age differences observed were at the lower and not higher nicotine dose. Our current and previous (Shram et al., 2007) findings suggest that nicotine may be less reinforcing in adolescent compared to adult rats. These results are quite different from CPP studies, including our own, demonstrating that adolescent rats are more responsive to the rewarding effects of nicotine compared to adult rats (Vastola et al., 2002; Belluzzi et al., 2004; Torrella et al., 2004; Shram et al., 2006; Brielmaier et al., 2007). A number of possibilities exist to help explain this apparent discrepancy. First, while the CPP and selfadministration paradigms are commonly used in parallel to measure the positive motivational effects of abused drugs, it is becoming increasingly evident that they are measuring different aspects of this process and are dissociable (Bardo and Bevins, 2000). Second, nicotine exposure in the self-administration paradigm occurs in multiple small doses, whereas it is administered in a single large dose in the CPP paradigm. Thus, the
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aversive (rate-limiting) effects of nicotine are likely weaker in the self-administration paradigm. Third, CPP studies involve passive exposure to nicotine, whereas in selfadministration studies nicotine intake is response contingent and voluntary. There are numerous examples in the literature demonstrating that drug responses may be different depending upon contingency of exposure (e.g., Dworkin et al., 1995; Jacobs et al., 2003). Passive compared to voluntary administration of nicotine may be more aversive in adult rats, as it is with cocaine (Lecca et al., 2007). The possibility of an interaction between contingency of exposure and age would be an intriguing area to explore in future studies. Developmental changes in mesolimbic dopamine (DA) function may help explain the age differences in the reinforcing effects of 0.015 mg/kg/infusion nicotine, since DA has been implicated in the incentive motivational processes involved in addiction to drugs (Robinson and Berridge, 1993; Berridge, 1996; Bechara et al., 1998; Di Chiara, 2000; Homberg et al., 2002; Wise, 2004), including nicotine (Fibiger and Phillips, 1988; Wise and Rompre, 1989). Nicotine administration, via its action at the nicotinic receptor (Pidoplichko et al., 2004), has been shown to increase DA release within the ventral and dorsal striata of rats (Yoshida et al., 1993; Pontieri et al., 1996; Di Chiara, 2000). Recently, age differences in potency of this effect have been reported (Azam et al., 2007), with the threshold for nicotine to stimulate DA release being higher in adolescent than in adult rat ventral striatum. If a minimum level of DA release is necessary to reinforce drug selfadministration, this finding would be consistent with our behavioural work indicating a reduced sensitivity to the low nicotine dose in adolescent rats. Azam and colleagues also observed that once the threshold was met, there was a greater nicotine-induced stimulation of DA release in the adolescent compared to adult ventral striatum. This may be due to a
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greater availability of DA since DA turnover is lower in adolescent (PD30) compared to adult ventral striatum (Teicher et al., 1993), although a more recent report using no net flux microdialysis indicates that basal DA is lower in adolescents (PD35, Badanich et al., 2006; but see Frantz et al., 2007). Thus, it remains possible that higher infusion doses of nicotine may be more reinforcing in adolescent compared to adult rats. Previous reports indicate that adult rats are more responsive to the aversive effects of nicotine withdrawal compared to adolescent rats (O'Dell et al., 2006; 2007a) and therefore, it is possible that their greater self-administration was partly driven to alleviate withdrawal effects (O'Dell et al., 2007b). This is unlikely however, since exposure to nicotine would have been minimal in the first few sessions and insufficient to produce dependence (Vann et al., 2006; O'Dell et al., 2007b). It is more plausible in the current case that the positive reinforcing effects of nicotine were driving lever responding, particularly considering that the age differences were only observed at the 0.015 mg/kg/infusion nicotine dose. Another possibility is that lower rates of lever responding under low FR reinforcement schedules are reflecting higher reinforcing efficacy (Yokel and Wise, 1975) of nicotine in adolescent compared to adult rats. This too however, is unlikely, since this effect would have extended to the 0.03 mg/kg/infusion dose of nicotine. The age differences reported here in male rats appear limited to nicotine since they did not generalize to a non-drug reinforcer, saccharin. Independent of strain, a similar proportion of adolescent and adult rats acquired saccharin self-administration and both groups responded similarly under the FR3 reinforcement schedule. Furthermore, saccharin intake, when corrected for body weight, was similar across age under the FR1 reinforcement schedule in both strains. It is important to note that adult rats responded
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more frequently on the active lever, and thus, would have earned more saccharin reinforcers under this schedule. However, a direct comparison of the absolute number of reinforcers earned by adolescent and adult rats would be difficult to interpret since adolescents would likely be sated following fewer saccharin reinforcers due to their smaller body size. Interestingly, saccharin intake by adolescent Wistar rats under the FR3 reinforcement schedule actually exceeded that of adult Wistar rats, providing further evidence that our findings with nicotine may not generalize to other non-drug reinforcers. Our results do not indicate an enhanced vulnerability to the reinforcing effects of nicotine during adolescence. These findings are similar to those recently reported for cocaine (Frantz et al., 2007; Kantak et al., 2007). Thus, as observed with other drugs of abuse, including cocaine and amphetamine (e.g., Infurna and Spear, 1979; Bolanos et al., 1996; Adriani and Laviola, 2003; but see Badanich et al., 2006), adolescents may exhibit a similar or blunted response to the motivational effects of nicotine compared to adults under specific conditions. Age differences in extinction and reinstatement of nicotine seeking To the best of our knowledge, this is the first report of extinction and priminginduced reinstatement of nicotine seeking during the adolescent period. Vehicle substitution resulted in decreased responding in both adolescent and adult rats. Interestingly, adult Wistar rats were more resistant to extinction compared to adolescent Wistar rats since they exhibited greater responding during the first trial of each extinction day. This is unlikely to be related to differences in the conditioned reinforcing effects of the nicotine-paired cue since both age groups earned a similar number of nicotine infusions (and similar nicotine-cue pairings). Adolescent and adult rats demonstrated similar
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reinstatement of nicotine seeking following a priming dose of nicotine, although not as robust as observed following lengthier between-session extinction procedures (Shaham et al., 1997; Le et al., 2006; Shram et al., 2007). Nevertheless, age at initiation does not appear to alter the relapse-inducing effect of a priming dose of nicotine (Shram et al., 2007) and this observation has now been extended to a second strain of rat. On the other hand, extinction of responding for saccharin depended upon age and strain. Within the LE strain, both age groups exhibited similar extinction of responding and this was similar to what was observed in the nicotine study. Interestingly, and in contrast with observations made within the nicotine study, adolescent Wistar rats were more resistant to extinction of responding compared to adult Wistar rats. The more persistent responding of the adolescent Wistar rats may potentially be related to their greater saccharin intake under the FR3 reinforcement schedule compared to adult rats. In the reinstatement tests however, priming with saccharin demonstrated a trend to increase responding on the saccharin-associated lever that was significant only in Wistar rats and was independent of age. These findings complement the age similarities in acquisition of saccharin self-administration. Concluding remarks Using an operant self-administration model, adult male rats more readily acquired nicotine self-administration compared to adolescent male rats at a lower infusion dose of nicotine (current study) and will lever press more for nicotine (Shram et al., 2007). Taken together, these findings indicate greater sensitivity to the reinforcing effects of nicotine in adulthood and challenge the concept of an enhanced vulnerability to nicotine addiction
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during adolescence. In humans, other factors, e.g., psychosocial and environmental, likely contribute to the high rates of smoking initiation during adolescence.
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Significance of chapter Initial sensitivity to the rewarding effects of abused drugs is an important predictor of vulnerability to continue use. In the spontaneous acquisition procedure, higher rates of acquisition are thought to reflect an enhanced vulnerability to the rewarding effects of abused drugs. This is the first study to successfully report the spontaneous acquisition of nicotine self-administration in adolescent rats of an outbred strain. This is also the first report to directly compare the spontaneous acquisition of nicotine self-administration in adolescent and adult rats in a limited access procedure using two infusion doses. In this study, we observed that adolescents were less sensitive to the direct reinforcing effects of a low infusion dose of nicotine compared to adult rats, but were similarly sensitive to the higher infusion dose tested. These findings demonstrated that adolescents are less susceptible to the reinforcing effects of low infusion doses of nicotine compared to adults. These observations were not related to developmental differences in performance since both age groups acquired self-administration of saccharin, an oral non-drug reinforcer. The results from this series of experiments suggest that adolescents may require higher doses to perceive the rewarding effects of response-contingent nicotine compared to adults. This may have important implications since frequency of smoking behaviour, e.g., more frequent puffs, may need to be greater to achieve a desired effect in adolescents compared to adults, who tend to puff harder or more quickly (Kassel et al., 2007b). The effects of repeated exposure to nicotine as well as the increased frequency of behavioural reinforcement may have a significant long-term impact on subsequent, more persistent, smoking behaviour.
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CHAPTER 6: ADOLESCENT AND ADULT RATS RESPOND DIFFERENTLY TO THE AVERSIVE EFFECTS OF MECAMYLAMINE-PRECIPITATED WITHDRAWAL
M.J. Shram, E.C.K. Siu, Z. Li, R.F. Tyndale and A.D. Lê Based on Psychopharmacology, submitted. All behavioural experiments, data analysis and manuscript writing were conducted by M.J. Shram. Plasma high performance liquid chromatography analysis of nicotine was performed by E.C.K. Siu and M.J. Shram. Z. Li assisted in completing the behavioural experiments. Initial study design was a collaborative effort between A.D. Lê and M.J. Shram. Additional design input was provided by R.F. Tyndale and E.C.K. Siu. A.D. Lê, E.C.K. Siu and R.F. Tyndale were involved in reviewing the manuscript prior to submission.
From: Shram et al. (2007) Adolescent and adult rats respond differently to the aversive effects of mecamylamine-precipitated withdrawal. Psychopharmacology, submitted. 161
Abstract Tobacco smoking typically begins during adolescence and such early onset is associated with a rapid progression to dependence. Although adolescents may exhibit a greater susceptibility to nicotine addiction, relatively little is known about the influence of the aversive effects of nicotine withdrawal. The present study investigated age differences in the motivational effects of mecamylamine-precipitated nicotine withdrawal in adolescent and adult rats using the CPA paradigm. Adolescent (PD28) and adult (PD60) male Wistar rats chronically treated with nicotine (3 or 6 mg/kg/day, s.c.) received mecamylamine (1 mg/kg, s.c.), a nicotinic receptor antagonist, or vehicle immediately prior to place conditioning. Nicotine withdrawal signs were also measured following administration of mecamylamine. A second experiment was conducted to increase nicotine levels in which adolescent rats were treated with 4.5 or 9 mg/kg/day nicotine. Nicotine-treated adult rats developed a CPA to the mecamylamine-associated compartment and expressed significant physical withdrawal signs, whereas similarly treated adolescents did not. Increasing nicotine exposure levels, confirmed by plasma nicotine measurements, did not modify the adolescent response to mecamylamine-precipitated withdrawal. The current study indicates that adolescent rats are less responsive to the aversive effects of mecamylamineprecipitated nicotine withdrawal compared to adult rats in the CPA paradigm and also exhibit weaker signs of physical withdrawal. These findings suggest that adolescents may be less susceptible to the aversive effects of withdrawal that promote continued smoking.
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Introduction Initiation of tobacco smoking during adolescence is associated with a number of long-term consequences including greater cigarette consumption, a reduced probability of quitting and an increased risk of relapse compared to later onset of tobacco use (Breslau and Peterson, 1996; Chen and Millar, 1998; Cui et al., 2006). Individuals who begin smoking during adolescence also experience a more rapid progression to dependence that may occur even prior to onset of daily smoking (Colby et al., 2000; DiFranza et al., 2000; Gervais et al., 2006). Although adolescents have only had a short history of exposure to smoking, many are unable to maintain abstinence (e.g., Burt and Peterson, 1998). Such epidemiological evidence suggests that adolescents may be particularly susceptible to nicotine addiction compared to older individuals. There is increasing experimental evidence derived from rodent models to suggest altered biological susceptibility to nicotine addiction during adolescence. Adolescence in the rat spans PD28 to PD42, although less conservatively, may extend up to PD55 (Spear and Brake, 1983; Spear, 2000). This developmental stage is characterized by unique behavioural and physical changes that parallel those observed in human adolescents, including increased risk-taking and impulsive behaviours, as well as a significant growth spurt (Spear, 2000). Moreover, the adolescent brain continues to mature, with further development of the mesocorticolimbic dopamine system (Teicher et al., 1995; Andersen et al., 2001; Leslie et al., 2004), which is strongly implicated in the reward and motivational processes of drug addiction (Di Chiara, 2000; Koob, 2003). Early work has suggested that adolescent rats find acute nicotine more rewarding and less aversive compared to adult rats (e.g., Levin et al., 2003; Belluzzi et al., 2004; Shram et al., 2006; Levin et al., 2007), but 163
more recent evidence under stringent self-administration conditions indicates that this may not be the case (Shram et al., 2007b), and that other factors, e.g., the aversive effects of nicotine withdrawal, may be contributing to the enhanced susceptibility to nicotine addiction during adolescence. The CPP paradigm is an important tool to measure the motivational effects of rewarding and aversive stimuli in rodents, including nicotine withdrawal (Suzuki et al., 1996; Ise et al., 2000; Watkins et al., 2000). Mecamylamine is a nAChR antagonist that can induce a significant withdrawal syndrome in nicotine-dependent rats (Hildebrand et al., 1997; Malin, 2001). This withdrawal state is sufficiently aversive to nicotine-dependent adult rats such that only one conditioning trial is necessary to produce a conditioned place aversion (CPA, Suzuki et al., 1996). Recently, O’Dell and colleagues (2007a) have observed that following multiple conditioning trials using a range of mecamylamine doses, adolescent rats, unlike adult rats, were insensitive to the aversive effects of precipitated nicotine withdrawal and did not express a CPA. In this study, chronic nicotine treatment was restricted to a single dose (3 mg/kg/day) that is sufficient to induce dependence in adult rats (e.g., Vann et al., 2006), but higher nicotine doses may be necessary to induce dependence in the adolescent rat. In the current study, we examined the influence of nicotine dose on potential age differences in mecamylamine-precipitated nicotine withdrawal. Specifically, we tested age differences in mecamylamine-precipitated CPA and assessed physical signs of nicotine withdrawal using a low dose of mecamylamine that is selective for the nAChR.
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Materials and Methods Animals Juvenile (PD21) and adult (PD53) male Wistar rats (Charles River, Quebec, Canada) arrived at the animal facility and were group-housed in Plexiglas cages measuring 51×41×20 cm. Juveniles were housed by litter (n=6 per litter) and adults were housed four per cage until surgery. The rats were maintained on a 12/12 h light/dark cycle (lights on at 1900 hours) in a temperature- and humidity-controlled vivarium. Water and Purina rat chow were available ad libitum throughout the experiment. All experimental procedures were carried out with the approval of the Centre for Addiction and Mental Health Animal Care Committee and in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. Apparatus The place conditioning boxes (30×60×40 cm) were made of Plexiglas and aluminum and composed of two compartments identical in size, separated by an elevated platform. One compartment was white and had a wire grid floor, while the other was black and had a floor with 1-cm holes set 1 cm apart. A removable partition was placed between the two compartments during conditioning, and a white-noise generator masked environmental noise. The time spent in each compartment was recorded using infrared photocell beams positioned equidistantly throughout the boxes during the conditioning and test sessions.
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Experiment 1 Adolescent (PD28, n = 48) and adult (PD60, n = 48) rats were surgically implanted with subcutaneous osmotic minipumps (type 2001, Alzet Osmotic Pumps, Cupertino, CA) designed to deliver a continuous infusion of nicotine for seven days, although unique specifications for the batch of pumps indicated that they would deliver solution for over nine days. To implant the minipumps, rats were first anaesthetized with isoflurane gas, a small incision was made between the shaved scapulae and the pump was inserted under the skin. The incision site was closed with wound clips and rats were allowed to recover from anaesthesia prior to returning to their homecage. Rats in the nicotine treatment groups were implanted with pumps set to deliver nicotine at an initial dose of 3 or 6 mg/kg/day nicotine, s.c., expressed as base. Control rats were implanted with a sham pump. On Day 7 of nicotine treatment, adolescent (PD34) and adult (PD66) rats underwent two place conditioning sessions. During conditioning, rats were treated with vehicle or mecamylamine (1 mg/kg, s.c.) and confined to one compartment for 60 min. Eight hours later, rats were confined to the opposite compartment immediately following administration of vehicle or mecamylamine. Injection order, i.e., mecamylamine or vehicle first, was counterbalanced across condition and compartment type. On the test day for place aversion, Day 8 of nicotine treatment, the partition was removed and each rat was placed on the central platform and allowed to freely explore the unpartitioned compartments for 15 min; no injections were given during the test. Adolescents were PD35 and adults were PD67 at time of testing. On the following day, withdrawal signs were recorded in rats that had not been exposed to mecamylamine during place conditioning. Withdrawal signs were assessed for 15 min following 1) vehicle and 2) mecamylamine (1 mg/kg, s.c.) administration as
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described by Malin et al. (1992) and Hildebrand et al. (1997). To measure nicotine levels and to correlate them with CPA magnitude, plasma samples were obtained from rats receiving mecamylamine during CPA conditioning and subsequently analyzed by HPLC as previously described (Siu et al., 2006). Briefly, trunk blood samples were collected by decapitation at the end of behavioural testing. Immediately after collection, plasmas were prepared by centrifugation at 3000 x g for 10 min and frozen at –20˚C until analysis. Total nicotine levels (free and glucuronides) were measured following deconjugation by β−glucuronidase at a final concentration of 5 mg/ml in 0.2 M acetate buffer, pH 5.0, at 37oC overnight. Plasma samples were extracted using ISOLUTE HM-N columns (Argonaut Technologies, Redwood City, CA, USA) with 13 ml of dichloromethane and were dried under nitrogen. Samples were reconstituted with 105 μl of 0.01 M HCl and 90 μl of each sample was analyzed by HPLC with UV detection (260 nm). Separation of nicotine was achieved using a ZORBAX Bonus-RP column (5 μm, 150×4.6 mm; Agilent Technologies, Mississauga, ON) and a mobile phase consisting of acetonitrile/potassium phosphate buffer (10:90 v/v, pH 5.07) containing 3.3 mM heptane sulfonic acid and 0.5% triethylamine. The separation was performed with isocratic elution at a flow rate of 0.9 ml/min. Nicotine sample concentrations were determined from standard curves. The quantitation limit for nicotine was 5 ng/ml. Experiment 2 Plasma nicotine levels were significantly lower in adolescent compared to adult rats in Experiment 1. Thus, in Experiment 2, we adjusted the nicotine dosing by a factor of 1.5 for the adolescents as per O’Dell and colleagues (2006), since they found this procedure to
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result in similar plasma nicotine levels in adolescent and adult rats following seven days of chronic nicotine exposure. In this second experiment, adolescents (PD28, n = 48) were implanted with minipumps set to deliver an initial dose rate of 0, 4.5 or 9 mg/kg/day nicotine. Behavioural procedures were similar to Experiment 1 with the exception that the observation period for withdrawal signs following vehicle and mecamylamine administration was increased to 30 min to assess a potential delayed onset of mecamylamine action in the adolescents. Plasma samples were taken on Day 8 of nicotine treatment due to inter-experiment variation in pump duration. Statistics and data presentation The results of the test for conditioned place aversion were calculated as difference scores (time on side paired with mecamylamine − time on side paired with vehicle) and analyzed by three-way ANOVA with the between-subjects factors of Age, Nicotine treatment and Mecamylamine. Withdrawal scores were calculated as the difference in withdrawal signs observed following mecamylamine and vehicle administration and subsequently analyzed by two-way ANOVA with the between-subjects factors of Age and Nicotine treatment. For post hoc tests, Tukey’s Honestly Significant Difference was used where appropriate. Statistical significance for all tests was set at α=0.05. Statistical analyses were performed using Statistical Package for the Social Sciences version 12.0.
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Results Experiment 1. Overall analysis of CPA in adolescent and adult rats revealed a significant Age x Nicotine treatment x Mecamylamine interaction (F(2,95) = 3.16, p < 0.05, Figure 18). Within the 6 mg/kg/day nicotine group, a significant Age x Mecamylamine interaction (F(1,27) = 5.89, p < 0.05) indicated that mecamylamineprecipitated nicotine withdrawal induced a CPA in adult, but not adolescent rats (F(1,14) = 10.36, p < 0.05). Mecamylamine administration alone did not induce a place preference or aversion. The expression of mecamylamine-precipitated withdrawal signs also depended upon Age (F(1,42) = 4.44, p < 0.05) and Nicotine treatment (F(2,42) = 6.49, p < 0.01). Mecamylamine administration precipitated withdrawal signs in nicotine-treated adults, but not in nicotine-treated adolescents (Figure 19). Within each nicotine treatment group, adults expressed greater withdrawal signs compared to adolescents (p < 0.05). Analysis of plasma samples revealed that adults had significantly higher nicotine levels on Day 9 of nicotine treatment compared to adolescents within the same nicotine treatment group (p < 0.001, Figure 20). Adolescents treated with 6 mg/kg/day nicotine however, had similar plasma nicotine levels at the end of the study compared to adults treated with 3 mg/kg/day nicotine. Considering this, a separate analysis compared CPA magnitude and withdrawal signs between these two groups (adolescents at 6 mg/kg/day nicotine and adults at 3 mg/kg/day nicotine) and their vehicle-treated controls. An Age x Mecamylamine interaction approaching significance (F(1,27) = 3.42, p = 0.075) indicated a trend for a mecamylamine-precipitated CPA in adults treated with 3 mg/kg/day nicotine,
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Figure 17. Mecamylamine-precipitated withdrawal place aversion in (a) adolescent and (b) adult rats chronically treated with 3 or 6 mg/kg/day nicotine. Datapoints represent mean (±SEM) time spent in the mecamylamine-paired compartment during the fifteen minute place aversion test. Open circles represent rats that received vehicle only during place conditioning and closed circles represent rats that received mecamylamine (1 mg/kg, s.c.) during one of two conditioning trials. Negative values indicate aversion to the mecamylamine-paired compartment (n = 7-8 per group) *p < 0.05 significantly different from vehicle administration.
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Figure 18. Mecamylamine-precipitated physical signs of withdrawal in adolescent and adult rats chronically treated with 3 or 6 mg/kg/day nicotine. Bars represent the mean (±SEM) difference score of withdrawal signs assessed following administration of vehicle and mecamylamine (1 mg/kg, s.c.). Each withdrawal assessment was fifteen minutes in duration. (n = 7-8 per group) *p < 0.05 significantly different from age-appropriate controls.
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Figure 19. Plasma nicotine levels in adolescent and adult rats chronically treated with 3 or 6 mg/kg/day nicotine. Bars represent mean (±SEM) plasma nicotine levels (ng/ml) obtained from samples taken at end of study (Day 9 of nicotine treatment). (n = 8 per group) *p < 0.05 significantly different from similarly treated adult rats.
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but not adolescents treated with 6 mg/kg/day nicotine. Analysis of withdrawal signs revealed an overall nicotine treatment effect (F(1,28) = 10.91, p < 0.01) that was significant in adults (p < 0.01), but not adolescents (p = 0.22), although comparison between the nicotine-treated adolescents and adults showed no difference in physical signs of withdrawal (p = 0.21). Experiment 2. Adolescents chronically treated with nicotine at an initial dose rate of 4.5 or 9 mg/kg/day did not express a mecamylamine-precipitated withdrawal CPA (F(2,42) = 0.931, p = 0.40, Figure 21a), nor did they show significant signs of withdrawal compared to controls (F(2,21) = 0.62, p = 0.55, Figure 21b). Adolescents initially exposed to 4.5 or 9 mg/kg/day nicotine had mean (± SEM) plasma nicotine levels of 42.1 (± 7.4) ng/ml and 92.7 (± 12.0) ng/ml, respectively, on Day 8 of treatment. Further analyses were conducted to compare the correlation between CPA magnitude and plasma nicotine levels from all rats in Experiments 1 and 2. Correlational analysis (Pearson’s) indicated that CPA magnitude was significantly related to nicotine levels in adult (r = -0.34, p = 0.05), but not adolescent rats (r = -0.029, p = 0.41).
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Figure 20. Mecamylamine-precipitated withdrawal place aversion and physical signs of withdrawal in adolescents chronically treated with 4.5 or 9 mg/kg/day nicotine. (a) Datapoints represent mean (±SEM) time spent in the mecamylamine-paired compartment during the fifteen minute place aversion test. Open circles represent rats that received vehicle only during place conditioning and closed circles represent rats that received mecamylamine (1 mg/kg, s.c.) during one of two conditioning trials. Negative values indicate aversion to the mecamylamine-paired compartment. (b) Bars represent the mean (±SEM) difference score of withdrawal signs assessed following administration of vehicle and mecamylamine (1 mg/kg, s.c.). Each withdrawal assessment was thirty minutes in duration. (n = 7-8 per group).
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Discussion The current study demonstrated that mecamylamine-precipitated withdrawal induces a significant CPA and physical signs of withdrawal in adult, but not adolescent, rats chronically treated with nicotine. The insensitivity of adolescent rats to the aversive effects of withdrawal was also maintained despite higher initial nicotine exposure levels. These results indicate that under the current testing conditions, adolescent rats may be less sensitive to the negative motivational effects associated with withdrawal that are involved in the maintenance of nicotine-taking behaviour. In Experiment 1, adult rats expressed a nicotine dose-dependent increase in CPA magnitude. These results are in agreement with previous work indicating that adult rats are sensitive to the aversive effects of mecamylamine-precipitated nicotine withdrawal, even after a single conditioning trial (Suzuki et al., 1996). Adolescent rats exposed to similar initial nicotine doses did not exhibit a CPA or an increase in physical signs of withdrawal compared to their age-appropriate controls. The absence of a CPA in nicotine-treated adolescent rats is unlikely to be related to age differences in learning since previous work has demonstrated that adolescent rats can express a conditioned place preference following one conditioning trial with nicotine (Belluzzi et al., 2004). A limitation of the first experiment was the significantly lower plasma nicotine levels of adolescent compared to adult rats receiving the same nicotine treatment. The lower levels of nicotine at time of sampling likely reflect the significant increase in body weight in adolescent rats across the seven day treatment period (~55%), which has been previously observed by O’Dell and colleagues (2006). Comparison of the withdrawal responses between the adult rats treated with 3 mg/kg/day nicotine and adolescent rats 175
treated with 6 mg/kg/day nicotine, which showed comparable plasma nicotine levels, revealed that adults rats showed a trend toward a CPA (p = 0.08), but not the adolescent rats. Adult rats treated with 3 mg/kg/day nicotine also expressed significantly more withdrawal signs compared to their age-appropriate controls, whereas adolescent rats treated with up to 6 mg/kg/day nicotine did not differ from their controls. In the second experiment, adolescents were treated with 4.5 or 9 mg/kg/day nicotine to compensate for the increase in body weight across treatment, a procedure previously used by O’Dell and colleagues (2006). However, even at this higher dose range, adolescents did not express a significant CPA, nor did they express an increase in physical withdrawal signs. To evaluate the relationship between nicotine levels and CPA magnitude, we compiled our CPA results from Experiments 1 and 2. CPA magnitude was significantly related to plasma nicotine levels in adult, but not adolescent rats. This finding further strengthens the idea that adolescent rats are less sensitive to the aversive effects of mecamylamine-precipitated withdrawal compared to adult rats, despite higher initial nicotine exposure levels. In contrast with previous work in adult rats (Skjei and Markou, 2003), increasing nicotine exposure did not alter the aversive effects of precipitated withdrawal in these younger rats. Although the second treatment regimen increased plasma nicotine levels in the adolescent rats, this did not yield levels within the same range as the adults in Experiment 1. This is unlikely to be attributable to inter-experiment variation in body weight gain, since the body weights of adolescents increased by approximately 55% in both experiments. Age differences in nicotine metabolism following chronic treatment cannot be excluded, but there do not appear to be large differences in N- or C-oxidation of nicotine
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between Wistar rats aged PD40 and PD100, in vitro in hepatic microsomes (Kyerematen et al., 1988). Interestingly, the kidney microsomes in that study showed slightly elevated total nicotine metabolism in adolescents compared to adults although its contribution in vivo was not established. It remains possible that other metabolic factors differ between adolescents and adults, such as other metabolic pathways, renal clearance or hepatic blood flow, which may account for the large age differences in plasma levels of nicotine. Adolescent rats appear less sensitive to the aversive effects of nicotine withdrawal, as measured by expression of a CPA, anxiety or physical signs (Wilmouth and Spear, 2006; O'Dell et al., 2007a), but they are more sensitive to its cognitive disrupting effects (Wilmouth and Spear, 2006). Taken together, these findings indicate that adolescent rats may undergo a withdrawal syndrome that is qualitatively different than that of adult rats. The experimental work demonstrating greater sensitivity to nicotine withdrawal in adult rats has employed mecamylamine to precipitate withdrawal. However, spontaneous nicotine withdrawal via active removal of the pumps delivering nicotine may yield different results, with both age groups exhibiting similar withdrawal signs in rats (Hamilton et al., 2006; Perry et al., 2006), but not mice (Kota et al., 2007), or greater sensitivity to the aversive cognitive disrupting effects of withdrawal in adolescent rats (Wilmouth and Spear, 2006). It remains possible that nicotine-dependent rats respond differently under spontaneous and precipitated withdrawal conditions. Such an observation is not novel, since differences between precipitated and spontaneous withdrawal have previously been reported in opioid and cannabinoid-dependent rats (Linseman, 1977; Mucha et al., 1979; Aceto et al., 1996).
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Age differences in the pharmacokinetics of mecamylamine cannot be ruled out, but are unlikely. Mecamylamine is excreted primarily as the unchanged parent compound by the kidney, reducing the likelihood of developmental differences in metabolism (Taylor, 1993). Moreover, the onset of drug action following subcutaneous administration is relatively rapid and our observation period of 30 min in Experiment 2 would be sufficient to capture the expression of physical signs of withdrawal (Hildebrand et al., 1997; Watkins et al., 2000). One potential mechanism for the increased sensitivity to mecamylamineprecipitated withdrawal in adult rats may be differential upregulation of nAChRs across development. Adolescent rats exhibit greater and more persistent nAChR upregulation following chronic nicotine treatment compared to adult rats (Trauth et al., 1999). If the behavioural effects of mecamylamine necessitate a threshold number of antagonized nAChRs, then perhaps higher doses of mecamylamine are required to elicit a withdrawal syndrome in adolescent rats. However, studies in adolescent and adult rats indicated that at doses greater than 1 mg/kg, mecamylamine may have non-specific effects (Watkins et al., 2000; Wilmouth and Spear, 2006; Matta et al., 2007). The observed age differences in mecamylamine-precipitated withdrawal CPA may be dependent upon developmental differences in the mesolimbic dopaminergic system (Stanwood et al., 1997; Spear, 2000; Teicher et al., 2003). Nicotine withdrawal has been shown to reduce dopamine release within this reward pathway (Fung et al., 1996; Hildebrand et al., 1999; Carboni et al., 2000a) and reductions in dopamine function may underlie withdrawal-induced CPA and changes in reward threshold (Stinus et al., 1990; Epping-Jordan et al., 1998). Developmental changes within the cholinergic system (Gould
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et al., 1991; Zhang et al., 1998; Azam et al., 2007) may also contribute to the age differences in nicotine withdrawal since cholinergic activity is altered during nicotine withdrawal in adult rats (Rada et al., 2001). Taken together, the current findings do not suggest a greater susceptibility to the aversive effects of nicotine withdrawal during adolescence. However, a lack of sensitivity to the aversive effects of withdrawal may promote continued use in adolescents since they are not deterred by the consequences of withdrawal. The observation that adult rats more readily develop physical dependence on nicotine is consistent with reports that abstinent adult smokers are more successful under nicotine replacement therapy (Silagy et al., 2004; Etter and Stapleton, 2006), whereas it does not significantly alleviate withdrawal symptoms in adolescents (Killen et al., 2001). The insensitivity of adolescent rats to nicotine withdrawal also agrees with previous works demonstrating a blunted response to the aversive effects of alcohol (Little et al., 1996; Acheson et al., 1999; Silveri and Spear, 2000), though adolescents may be more vulnerable to the cognitive effects of both drugs (White and Swartzwelder, 2005; Wilmouth and Spear, 2006). Further investigation is necessary to evaluate the influence of nicotine withdrawal on continued smoking behaviour in adolescents and how it may differ qualitatively from adult symptomatology.
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Significance of chapter Withdrawal from nicotine can result in a number of physical, affective and cognitive consequences that motivate continued smoking behaviour. Adolescents may be differentially sensitive to the aversive effects of nicotine withdrawal, which might contribute to their increased susceptibility to nicotine addiction. This study investigated age differences in the aversive effects of mecamylamine-precipitated withdrawal by measuring CPA and physical signs in adolescents and adult rats chronically treated with nicotine. Adolescent rats did not demonstrate a CPA, nor did they show significant physical signs of withdrawal. In contrast, adult rats exhibited significant CPA and physical signs, effects that were dependent upon nicotine treatment dose. Although adolescents had significantly higher initial exposure to nicotine, nicotine levels were significantly lower in adolescent compared to adult rats at the end of the study. Differences in body weight gain are likely playing a large role in the age differences in nicotine levels, but we cannot rule out developmental differences in metabolism following chronic administration of nicotine. Despite this, these findings provide further support to previous studies indicating that adolescents are less sensitive to the aversive physical and affective properties of nicotine withdrawal, but also point out that there may be developmental differences in the sensitivity to mecamylamine.
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CHAPTER 7 GENERAL DISCUSSION Adolescence is a unique stage in the initiation and maintenance of smoking. A variety of factors have been identified that interplay to promote smoking during this period of rapid development and maturation. Psychosocial influences, as well as behavioural characteristics of adolescence, have a strong impact on the initiation of smoking. In addition to these factors, adolescents may also exhibit a biological susceptibility to the motivational effects of nicotine and its withdrawal, since adolescent onset of smoking is associated with a more rapid progression to dependence, a reduced probability of quitting and an increased risk of relapse compared to later onset (Breslau and Peterson, 1996; Chen and Millar, 1998; Colby et al., 2000; Cui et al., 2006). Therefore, the focus of the current thesis was to test the hypothesis of a biological susceptibility to nicotine taking during adolescence by systematically investigating the processes involved in the acquisition and maintenance of nicotine taking behaviour using a rat model. Under the current experimental conditions, we observed that adolescent rats are more responsive to the conditioned rewarding effects of nicotine and are less sensitive to its aversive effects compared to adult rats. Further to this, acute nicotine administration had greater activational effects within reward-related substrates in adolescent compared to adult rat brain. These findings suggest that adolescents may be more responsive to the rewarding effects of nicotine that play an important role in the acquisition of nicotine taking. Both adolescent and adult rats self-administered nicotine under a variety of reinforcement schedules, but nicotine had greater reinforcing efficacy in adult rats as evidenced by the greater BP achieved by these older animals. Although both adolescent and adult rats spontaneously acquired self-administration of a commonly used maintenance dose of
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nicotine, adult rats were more sensitive to the reinforcing effects of a threshold dose of nicotine. The findings under self-administration conditions therefore suggest that adults are more responsive to the direct reinforcing effects of nicotine. However, independent of age at onset of self-administration, re-exposure to nicotine reliably reinstated nicotine seeking behaviour. Finally, in our assessment of age differences in mecamylamine-precipitated withdrawal, adolescent rats were less sensitive to the aversive effects of nicotine withdrawal compared to adult rats. This latter finding suggests that adults may be more likely to maintain nicotine use in order to alleviate negative withdrawal symptoms.
SECTION 9 AGE DIFFERENCES IN FACTORS INFLUENCING ACQUISITION OF NICOTINE TAKING The initial response to the pharmacological effects of abused drugs is an important factor in the vulnerability to addiction (Deminiere et al., 1989; Bozarth, 1990). The rewarding effects of abused drugs, including nicotine, are significant contributors in the likelihood of initiating use, whereas the aversive effects may limit use. Therefore, we first investigated whether adolescent and adult rats respond differently to the rewarding and aversive effects of nicotine. Several lines of evidence indicate that nicotine is more rewarding in adolescent compared to adult rats. First, adolescents more readily expressed a nicotine-induced CPP, indicating that they were more sensitive to the rewarding effects of nicotine compared to adults (Shram et al., 2006). In contrast, adolescents were insensitive to the aversive effects of nicotine, as measured in the CTA paradigm. Consistent with a number of previous reports, adult rats did not readily demonstrate a CPP using the unbiased procedure, but showed significant sensitivity to the aversive effects of nicotine using the CTA procedure. 182
Second, we observed that acute nicotine administration, within the same dose range used in the conditioning experiments, preferentially activated neural substrates implicated in the rewarding effects of abused drugs within adolescent compared to adult rat brain, as measured by increases in c-fos mRNA expression (Shram et al., 2007a). These findings would be consistent with the hypothesis of an enhanced vulnerability to the rewarding effects of nicotine during adolescence. Having observed an age-dependent response to the rewarding effects of nicotine using traditional conditioning procedures, we then assessed age differences in the direct reinforcing effects of nicotine using the gold standard operant intravenous selfadministration procedure. Both adolescent and adult rats readily self-administered nicotine (0.03 mg/kg/infusion) under low FR reinforcement schedules, indicating that nicotine is equally reinforcing across the two ages tested under response-contingent conditions (Shram et al., 2007b). Responding for this same infusion dose of nicotine was similar across age in a spontaneous acquisition procedure, providing further evidence that the reinforcing effects of this dose of nicotine are similar in adolescent and adult rats (Shram et al., 2007c). However, when response costs increased to the more taxing FR5 and PR reinforcement schedules, clear age differences emerged, with adults willing to work harder for nicotine compared to adolescents. This important and novel finding suggests that adult rats are more motivated to seek and obtain nicotine, despite being more sensitive to its aversive effects. Taken together, the paradoxical findings obtained under CPP and self-administration conditions have generated a number of questions to challenge the hypothesis of a greater biological susceptibility to the motivational effects of nicotine during adolescence.
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SECTION 9.1 PARADOXICAL FINDINGS IN AGE DIFFERENCES IN THE REWARDING EFFECTS OF NICOTINE There are several important and notable differences between CPP and selfadministration that may account for the findings obtained with these two commonly used procedures. First, the learning process differs significantly between CPP and selfadministration. CPP relies on classical conditioning and is an important index of the ability of drug-associated contextual cues to elicit approach or avoidance responses (Bozarth, 1987). Thus, the conditioned effects of nicotine are measured during the drug-free preference test. In contrast, the self-administration paradigm is dependent upon operant conditioning in which the direct effects of nicotine are reinforcing behaviour (i.e., lever pressing), since testing occurs in the presence of the nicotine. Adolescent and adult rats are capable of learning under both classical and operant conditions (e.g., Laviola et al., 1992; Kantak et al., 2007), suggesting that general age differences in learning each procedure are unlikely to have played a significant role in the behavioural findings presented here. Second, the method of nicotine administration is markedly different in these two procedures. In CPP, nicotine is administered by the experimenter and thus, not contingent upon the rat’s behaviour. On the other hand, the self-administration paradigm, by definition, involves active intake of nicotine. The behavioural and neurochemical responses to response-independent drug administration have been reported to be quite different from response-contingent drug in both humans and animals (Dworkin et al., 1995; Donny et al., 2000; Jacobs et al., 2003; Donny et al., 2006; Lecca et al., 2007). For example, adult rats self-administering cocaine do not develop stereotyped behaviours as readily and show reduced mortality compared to rats passively exposed to the same amount of drug in a yoked design (Dworkin et al., 1995; Lecca et al., 2007). These reports suggest that the 184
aversive effects of cocaine are experienced differently depending upon whether the drug is administered passively or actively. Nicotine can also elicit different neurochemical and behavioural effects depending upon administration contingency (Donny et al., 2000). Therefore, method of administration may be an important factor contributing to the differences we observed when comparing our findings using these two procedures. Although not directly tested, the age differences we observed in the CTA paradigm may be indicative of developmental changes in sensitivity to the aversive effects of nicotine depending upon whether it is administered passively or actively. Third, although the total amount of nicotine typically self-administered intravenously (0.6-0.8 mg/kg/day) was similar to that delivered subcutaneously by the experimenter in the CPP and CTA paradigms (0.4-0.8 mg/kg), the peak nicotine levels would be significantly higher following a single subcutaneous injection. Therefore, the effects of nicotine, rewarding or aversive, would be experienced more intensely following one injection compared to multiple, self-paced infusions. Additionally, it is likely that the aversive effects of the low intravenous doses are weaker under self-administration conditions and also under the control of the rat. Considering this, the aversive effects of nicotine would play a smaller role in the self-administration paradigm compared to the passive CPP and CTA procedures, which may help explain the similar self-administration behaviour of adolescent and adult rats under the simple FR reinforcement schedules. Under higher reinforcement schedules however, processes in addition to sensitivity to the simple hedonic or primary rewarding effects of nicotine are recruited, with motivation or effort to obtain nicotine becoming progressively more important in maintaining self-administration behaviour (Salamone et al., 2007).
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SECTION 9.2 AGE DIFFERENCES IN THE MOTIVATION TO SELFADMINISTER NICOTINE In our first self-administration experiment, nicotine (0.03 mg/kg) was equally reinforcing in adolescent and adult rats when using low reinforcement schedules (FR1/FR2). However, significant age differences emerged when the demand increased. Adults were willing to work harder to obtain nicotine (e.g., FR5), and consistently reached higher BP compared to adolescents in the PR tests (e.g., 107 vs. 32), indicating greater reinforcing efficacy of nicotine in adult compared to adolescent rats. Our findings have highlighted dramatic age differences in the motivation to selfadministration nicotine that did not generalize to a non-drug reinforcer saccharin, for which BP were similar across age. The possibility that adolescent humans are similarly less motivated to obtain nicotine has previously been suggested since they are the most sensitive age group to increasing cigarette costs and most likely to seek noncommercial (and easier) sources of cigarettes (Castrucci et al., 2002; Ding, 2003). Such observations should not be taken lightly because they suggest that adolescent nicotine taking may be inelastic, and changes in cost may have significantly greater influence upon the likelihood of continued smoking during this developmental period.
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Section 9.2.1. Age differences in the motivation to self-administer nicotine: Potential role for dopamine The motivational processes in drug addiction, and acquisition of appetitive stimuli in general, appear to be dependent upon normal functioning of the mesocorticolimbic DA system (Berridge, 1996; Bechara et al., 1998; Di Chiara, 2000; Homberg et al., 2002; Wise, 2004). However, the DA system continues to mature during adolescence. During this time there appears to be a shift from subcortical to cortical DA influence; DA function increases within PFC, but is also accompanied by reduced NAC DA activity (Kalsbeek et al., 1988; Teicher et al., 1993; Teicher et al., 1995; Benes et al., 2000). The hypodopaminergic state of the adolescent NAC may help explain the age differences observed in self-administration under high response costs (FR5/PR). Elegant work examining the role of NAC DA in food motivated responding indicates that DA lesions of the NAC do not alter the rewarding or hedonic aspects of food, which are thought to be mediated by opioidergic mechanisms (Berridge and Robinson, 2003) but instead, alter the motivation to obtain food reinforcement (Salamone et al., 1997; Aberman and Salamone, 1999). For example, NAC-lesioned rats will still consume food and respond under a FR1 reinforcement schedule similarly to sham-lesioned rats, but are selectively impaired when responding under higher response costs, e.g., under a PR reinforcement schedule (Aberman and Salamone, 1999). Similar to lesioning techniques, pharmacological manipulations of DA, e.g., intra-NAC agonist or antagonist administration, can increase or decrease, respectively, the motivation (measured by BP) to obtain food reinforcements (Zhang et al., 2003). These findings are analogous to the behavioural data obtained with adolescent rats self-administering nicotine, which showed high responding under the FR1 187
reinforcement schedule, indicating that nicotine is reinforcing, but significantly reduced responding under the FR5 and PR reinforcement schedules. Considering the behavioural similarities between our adolescent rats and NAC-lesioned adult rats, it is tempting to speculate that the hypodopaminergic state within NAC of adolescent rats may have influenced behavioural responding under high response costs in the nicotine selfadministration paradigm. Similarly, 6-hydroxydopamine NAC lesions reduce nicotine selfadministration under a FR5 reinforcement schedule (Corrigall et al., 1992), though this has not been examined under a FR1 reinforcement schedule. Nicotine has primarily activational effects via the neuronal nAChR in reward circuitry, increasing firing rates of VTA DA neurons resulting in the release of DA in NAC, striatum and other regions (Pidoplichko et al., 1997; Pidoplichko et al., 2004). This DA elevating effect is a common feature of all drugs of abuse tested thus far (Di Chiara and Imperato, 1988). Several reports indicate a role for DA in the rewarding effects of nicotine, but cumulatively, the evidence has suggested that DA may play a more significant role in its incentive motivation, a process by which goal-directed behaviours are controlled by incentives and associated stimuli (Robinson and Berridge, 1993). DA blockade does not consistently affect acquisition of nicotine CPP (e.g., D1 antagonist SCH 39166 vs. D2 antagonist sulpiride, Spina et al., 2006), during which associative learning occurs between the environment and nicotine’s effects. It does however, block the expression of a CPP (e.g., D3 antagonist SB-277011A, Le Foll et al., 2005; Pak et al., 2006), indicating that DA release associated with nicotine-associated stimuli may be important in eliciting approach or avoidance behaviour. D1 blockade prevents the acquisition of nicotine CPP, but it also
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prevents acquisition of a CPA to aversive stimuli, indicating that the antagonism is not affecting the hedonic or primary rewarding effects of appetitive stimuli, but perhaps their salience (Acquas et al., 1989). Under self-administration conditions, administration of DA antagonists more consistently reduces behavioural responding for nicotine (Corrigall and Coen, 1991; David et al., 2006; Ikemoto et al., 2006; Ross et al., 2007). However, it must be noted that the majority of self-administration studies indicating a role for DA in nicotine reinforcement have employed higher response costs (e.g., FR5 and PR), whereas a study using a low reinforcement schedule has found no effect of DA blockade on nicotine self-administration (Andreoli et al., 2003). It may be tenuous to suggest that DA blockade is selectively suppressing the motivation to obtain nicotine because very few nicotine self-administration studies have examined DA blockade under low reinforcement schedules, which would better examine the role of DA in mediating its primary rewarding effects. That being said, DA may play a smaller role in the rewarding or hedonic aspects of nicotine, as evidenced by CPP studies, whereas it may be more significant in modulating its reinforcing effects or incentive motivation, e.g., the motivation to obtain nicotine under more taxing conditions. Several other neurotransmitter systems have been implicated in nicotine’s rewarding effects, including the cholinergic (Picciotto et al., 1998; Corrigall et al., 2001; Blokhina et al., 2005; Walters et al., 2006), glutamatergic (Papp et al., 2002; Tessari et al., 2004; Blokhina et al., 2005), GABAergic (Corrigall et al., 2000; Fattore et al., 2002; Paterson and Markou, 2005; Mombereau et al., 2007), cannabinoid (Castane et al., 2002; Forget et al., 2005), opioid (Corrigall et al., 2000; Berrendero et al., 2005) and possibly serotoninergic systems (Carboni et al., 1989; Corrigall and Coen, 1994). The degree to
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which one can effectively tease apart the hedonic and incentive motivational effects of nicotine based on these data is limited, considering that most self-administration studies employ higher reinforcement schedules. However, based upon the CPP studies and the limited self-administration studies using low FR reinforcement schedules, it would appear that other neurotransmitter systems are important in the hedonic aspects of nicotine, whereas the motivation to self-administer nicotine may rely upon adequate DA function, as has been observed with other abused drugs (e.g., cocaine, Xi et al., 2005). We did not examine age differences in nicotine-induced DA release. However, others have observed that, using microdialysis, passive acute nicotine administration (0.6 mg/kg) increases DA concentrations in NACs of adult, but not adolescent rat brain (Badanich and Kirstein, 2004). This suggests that adolescents are less sensitive to the DA releasing action of nicotine, but such a conclusion must be tempered by the analytical methodology used. In this study, mean area under the curve was used to analyze changes in DA levels following nicotine administration, which would not consider temporal changes across the 120 minute sampling period. A more detailed analysis following cocaine administration (5 mg/kg, i.p.) has demonstrated that cocaine increases DA in NAC of both adolescent (PD35 and PD45) and adult (PD60) rats, however the time course of DA increases differed across development (Badanich et al., 2006). Cocaine produced an earlier peak in DA concentrations in adolescent compared to adult rats. Furthermore, peak DA levels decayed more rapidly in these younger rats, whereas the increase was sustained in the adults. Should this pattern be similar following nicotine administration, the resultant gross analysis of area under the curve previously reported for nicotine would not have captured these ontogenetic differences in DA response. More recently, Frantz et al. (2007)
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demonstrated that DA release, measured over time in NAC by microdialysis, was similar in adolescent and adult rats following passive intravenous administration of cocaine (at selfadministered doses). Although the mechanism of action of cocaine differs from that of nicotine, both require increased DA release in NAC for their reinforcing properties (Di Chiara and Imperato, 1988). Taking this into consideration, it would be difficult to argue that nicotine does not increase DA concentrations in NAC of adolescent rats, particularly since they will readily self-administer nicotine. Recent evidence does however, indicate developmental differences in nicotine’s DA releasing action within NAC. At PD30, the mean effective concentration (EC50) of nicotine required to release DA in vitro (5.75 μM) is significantly greater compared to that at adulthood (2.37 μM), yet the amount released is higher (7.5 vs. 4.3%, Azam et al., 2007). Thus, there are functional differences in the DA response to nicotine administration that may help explain the differences in motivation to self-administer nicotine between adolescents and adults. Adolescent rats would likely require more nicotine to achieve DA release within the NAC, but once the threshold is attained, then the greater release may lead to greater reinforcing effects of nicotine or greater motivation to obtain nicotine under selfadministration conditions. A differential sensitivity to nicotine-induced changes in DA release might also explain the failure of adolescent rats to spontaneously acquire nicotine self-administration at the lower infusion dose (0.15 mg/kg). It is possible that this lower dose produces less DA release in adolescent compared to adult NAC that would be important in reinforcing selfadministration behaviour. Given a threshold dose of nicotine however (e.g., 0.03 mg/kg), self-administration behaviour was similar between adolescent and adult rats. The greater
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DA release associated with higher dose nicotine administration in adolescent brain may also explain the expression of CPP to this reinforcer in adolescent rats at the 0.4 and 0.8 mg/kg doses (Belluzzi et al., 2004; Shram et al., 2006). In addition to its role in incentive motivation, DA has recently been reported to mediate the aversive effects of nicotine. For example, intra-VTA DA receptor antagonism can reverse a nicotine-induced place aversion to a preference and can block a CTA to a nicotine-paired solution in adult male rats (Laviolette and van der Kooy, 2003). Mature DA function may therefore result in greater sensitivity to the aversive effects of nicotine. This possibility may account for the robust CTA induced by nicotine in adult, but not adolescent rats, and could also help explain age differences in the expression of a nicotine CPP. If adolescents, with an immature mesocorticolimbic DA system, are less responsive to (aversive) nicotine-induced DA release, they may be more apt to experience the positive rewarding effects of nicotine, resulting in the expression of a CPP. On the other hand, adult rats would experience both the rewarding (potentially DA-independent) and aversive effects of nicotine, the net balance of which could lead to the absence of a CPP. Thus, taken together with the idea that mature DA function is necessary to perform successfully under taxing reinforcement schedules, these findings may help explain why adolescent rats are insensitive to the aversive effects of nicotine and are also less motivated to selfadminister it under taxing conditions compared to adult rats.
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SECTION 9.3 AGE DIFFERENCES IN THE SENSITIVITY TO NICOTINE Nicotine CPP has been readily demonstrated in adolescent rats (Vastola et al., 2002; Belluzzi et al., 2004; Torrella et al., 2004; Shram et al., 2006), but it has proven difficult to establish a robust, consistent nicotine CPP in adult rats using a variety of procedures and doses (for review, Le Foll and Goldberg, 2005). Based on these reports, it may be hypothesized that adolescents are more sensitive to the rewarding effects of nicotine compared to adults. However, the CPP paradigm measures the net motivational effects of a stimulus (Tzschentke, 1998). Therefore, the interplay between the rewarding and aversive effects of nicotine would be an important determinant of nicotine’s overall motivational valence and how it might control behaviour (approach or avoidance). The absence of CPP in adult rats may therefore simply reflect their greater sensitivity to the aversive effects of passively administered nicotine, rather than a reduced sensitivity to its rewarding effects per se. This would be supported by experimental evidence obtained using the CTA procedure (Wilmouth and Spear, 2004; Shram et al., 2006). Alternatively, adolescents may develop tolerance to the aversive effects of nicotine more rapidly following repeated administration (4 injections) compared to adults, which would attenuate the expression of a CTA and increase that of a CPP. Previous reports however, indicate that adolescent rats can demonstrate a nicotine CPP following a single conditioning trial (Belluzzi et al., 2004; Brielmaier et al., 2007), and thus, argue against this latter possibility. Reduced sensitivity to some of nicotine’s effects in adolescents has also been observed in tests other than the CTA and self-administration. Kota et al. (2007) reported that adolescent mice were less sensitive to the antinociceptive effects of nicotine in the tail flick test (spinal antinociception) and that they developed greater tolerance in the hot plate 193
test (supraspinal antinociception) compared to adult mice. Not all of nicotine’s effects are necessarily dependent upon age however, e.g., hypothermia (Kota et al., 2007). These findings suggest that age-dependent sensitivity to nicotine’s effects is selective and should not be generalized. It is also possible that passively administered nicotine (0.25-0.5 mg/kg) has more anxiolytic effects in adolescents in the social interaction test (Cheeta et al., 2001, but see Adriani et al., 2004; Cao et al., 2007 for results obtained using the elevated plus maze), whereas it may have a greater anxiogenic profile in adults (File et al., 2000). This difference could play an important role in the expression of CPP, particularly under biased conditions (Vastola et al., 2002; Torrella et al., 2004), in which nicotine may preferentially alleviate the anxiety associated with the initially non-preferred compartment in adolescent rats or alternatively, induce anxiety in adults independent of the conditioning procedure (biased or unbiased). Nicotine activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased glucocorticoid release in humans (cortisol, Pomerleau and Rosecrans, 1989) and rodents (corticosterone (CORT), Balfour et al., 1975). Interestingly, Cao et al. (2007) have shown that passive nicotine administration (0.03 mg/kg, i.v.) increases CORT levels in adult rats, but fails to do so in juvenile rats (PD27). Although not tested directly, these findings may indicate that the adolescent CORT response to nicotine is attenuated compared to that of adults. While not yet demonstrated experimentally, it is possible that CORT may influence sensitivity to the reinforcing properties of nicotine. Sensitivity to cocaine under selfadministration conditions is positively correlated with CORT levels and acquisition of
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cocaine self-administration does not occur until a threshold CORT level is reached (Goeders, 2002). Furthermore, this facilitatory effect of CORT is specific to acquisition of low doses of cocaine, with no appreciable changes occurring at higher doses (Goeders and Guerin, 1996). An attenuated CORT response to nicotine might therefore help explain the reduced sensitivity of the adolescent rats to the low infusion dose of nicotine in the spontaneous acquisition study. If a critical CORT threshold is required to initiate nicotine self-administration, as it appears to be with cocaine, then the 0.015 mg/kg dose of nicotine may be too low for the adolescent rats since it may not sufficiently increase CORT levels.
SECTION 9.4 DEVELOPMENTAL DIFFERENCES IN COGNITION AND POSSIBLE INTERACTIONS WITH NICOTINE The brain matures during adolescence and is associated with continued cognitive development in both humans and rodents. Such cognitive immaturity could thus potentially explain some of the differential effects we observed in the CPP and self-administration experiments. The PFC is involved in executive functions and goal-directed behaviours (Bechara et al., 1999) and undergoes development during adolescence, with continued myelination, synaptic pruning and increasing neural inputs (Sowell et al., 1999; Giedd, 2004; Gogtay et al., 2004; Markham et al., 2007). The PFC is also important in novel or demanding situations, particularly those that require flexibility in behaviour when demands or response contingencies change (Rolls, 2004). Self-administration, particularly that under PR testing conditions, requires the rat to direct its behaviour and modify its responding under changing reinforcement contingencies. Therefore, it is possible that the reduced BP in adolescent rats self-administering nicotine may reflect a failure to respond to the rapidly 195
changing reinforcement contingencies under PR testing conditions due to immature PFC function (for brief review, see Spear and Brake, 1983). The similarity in PR responding for saccharin in adolescent and adult rats however, would suggest that the adolescent rats are able to process the change in reinforcement contingency, but this possibility cannot readily excluded due to the lower BP achieved with this non-drug reinforcer. Alternatively, adolescent rats may exhibit greater attentional deficits, which could result in reduced responding during the lengthy (2 hr) PR sessions. This possibility may be ruled out since spontaneous acquisition self-administration sessions were of the same duration and responding was maintained throughout these operant sessions by both age groups. On the other hand, adolescents may be more susceptible to extinction under appetitive responding conditions compared to adults (Spear and Brake, 1983). PR testing may be considered a form of extinction (Sizemore et al., 2003), because it becomes increasingly difficult to earn reinforcers and the BP itself is a measure of when the rat ‘gives up’. General developmental differences in extinction of appetitive responding may be unlikely however, as we observed similar extinction of saccharin responding in adolescent and adult rats of two different strains. Spear and Brake (1983) have suggested that adolescents may exhibit an immature ability to focus attention on spatial and discriminative cues, and this possibility could help explain the lower BP achieved in the self-administration experiments. While this idea is supported by findings under certain conditions (e.g., Schochet et al., 2004), it may be less likely under other conditions, since adolescents show significant CPP to a variety of abused drugs (Laviola et al., 1992; Campbell et al., 2000; Belluzzi et al., 2004; Shram et al., 2006), a procedure that involves associative learning between contextual cues and a drug’s effect
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during conditioning and discrimination between two distinct compartments during the preference test. On the other hand, adolescent rats may be differentially responsive to the discrete cues used in the self-administration paradigm. Arguing against this possibility is that adolescents can develop CTA a sweet solution paired with amphetamine (Infurna and Spear, 1979), indicating that adolescents can make associations between stimuli and discrete cues. Developmental differences in nicotine’s effects upon attention, learning and memory processes could possibly account for some of the behavioural differences we observed under self-administration conditions. Much preclinical work using adult rats has examined the role of the cholinergic system in cognitive processes, with acute and chronic nicotine having beneficial effects in tasks measuring sustained attention, working memory and reaction time (for review, see Levin et al., 2006). For example, in adult rats, nicotine improves sustained attention in the five choice serial reaction time task under low event rate conditions, when vigilance is being taxed (Mirza and Stolerman, 1998). Interestingly, this nicotine-induced attentional enhancement is selectively mediated by the PFC (Hahn et al., 2003). Therefore, adults may be more responsive to the attention enhancing effect of nicotine compared to adolescents, whose PFC is still developing. Such a possibility may have contributed to the more persistent behavioural responding of adult rats in the PR tests, when attention was being taxed due to the high work demand. Such effects however, remain to be tested in adolescents and cannot as yet adequately explain our current PR results. In addition to its ability to improve cognitive function, nicotine has been reported to support self-administration behaviour through two paths: 1) its primary reinforcing effects
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and 2) its ability to enhance the reinforcing value of stimuli (CS) associated with nicotine delivery. Nicotine and its associated CS (e.g., light+tone) are known to act synergistically on operant responding in adult rats, suggesting that nicotine ‘brightens’ an intrinsically reinforcing stimulus in addition to being reinforcing itself (Caggiula et al., 2001). Such an effect appears to be a distinct property of nicotine, since the intrinsic reinforcing effects of cues are simply additive to the direct reinforcing effects of cocaine (Deroche-Gamonet et al., 2002). This property of nicotine may be experienced differently in developing adolescent rats, which may account for the age differences observed under selfadministration conditions. Although this possibility may not account for the similar priming-induced reinstatement of nicotine seeking, this greater reinforcement enhancing effect, combined with the primary reinforcing properties of nicotine, could explain some of our self-administration findings e.g., responding under the FR5 and PR reinforcement schedules, and greater acquisition by adult rats at the low infusion dose of nicotine.
SECTION 9.5 PHARMACOKINETIC DIFFERENCES Pharmacokinetic differences can play a significant role in drug taking behaviour, including nicotine. For example, increased metabolism of nicotine is associated with more frequent smoking since more nicotine intake is needed to achieve the desired plasma nicotine levels. Slower metabolism on the other hand, is associated with fewer cigarettes consumed and a lower probability of dependence (Schoedel et al., 2004). It is possible that the differences between adolescent and adult rats in nicotine-motivated behaviour are related to differences in the pharmacokinetics of nicotine. While not specifically examined, there are a number of arguments against this idea. First, differences in absorption are precluded in the intravenous self-administration paradigm since administration is directly 198
into the vasculature. Second, following subcutaneous administration, the time to peak concentration is rapid (Tmax ~5 min in adult rats, Turner, 1975). Our behavioural procedures would have captured this period and thus, both age groups would have the opportunity to experience the rewarding effects of nicotine within the specified time constraints (e.g., 20 min in CPP conditioning sessions). Additionally, in the CTA procedure, nicotine administration occurred after CS exposure, an association that would not likely have been affected by age differences in the onset of nicotine action. Further to this, intravenously administered nicotine at a dose used in self-administration experiments, which would have very rapid onset and offset of action, can induce a CPP in adolescent, but not adult rats (Shram and Lê, in preparation). These observations indicate that the onset of action is an important determinant of the rewarding effects of nicotine (Shoaib, 1996; Samaha et al., 2005) and is not likely to differ significantly between adolescents and adults, particularly when administered intravenously. It remains possible that differences in metabolism or clearance played a role in the differences observed under self-administration conditions, but significant differences were only observed at high response costs (FR5/PR) and not under FR1 or FR2 reinforcement schedules. If metabolic differences were playing a large role, we would expect to see consistent age differences across reinforcement schedules and infusion doses. In vitro studies examining age differences in C- and N-oxidation of nicotine, two important metabolic pathways in rat, have not shown significant differences in metabolism between PD40 and PD100 within the two strains of rat (Wistar and Long Evans) employed in the current series of experiments (Kyerematen et al., 1988). Interestingly, Sprague Dawley rats show age-dependent differences in nicotine pharmacokinetics (Kyerematen et al., 1988;
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Cao et al., 2007). This observation may partly explain why other experimenters have reported greater nicotine self-administration in adolescent compared to adult Sprague Dawley rats under FR1 reinforcement schedules (Levin et al., 2003; Levin et al., 2007). Slower metabolism of nicotine, as suggested by Wilmouth and Spear (2006), could possibly explain the lower BP achieved by adolescents, but this would not be consistent with the reduced spontaneous acquisition of self-administration of 0.015 mg/kg nicotine, nor with the suggestion that adolescents metabolize nicotine more rapidly (Trauth et al., 1999; Slotkin, 2002).
SECTION 9.6 AGE DIFFERENCES IN THE EFFECTS OF NICOTINE WITHIN THE CONTEXT OF ADOLESCENT SUSCEPTIBILITY TO DRUGS OF ABUSE The rewarding effects of a variety of abused drugs have now been examined in adolescent and adult rodents. Although increased sensitivity to the rewarding effects of abused drugs is thought to reflect an enhanced vulnerability to addiction (Piazza et al., 1989), adolescents appear to have a blunted response to the rewarding effects of amphetamine and opioids in CPP compared to adults (Spear and Brake, 1983; Bolanos et al., 1996; Adriani and Laviola, 2000, 2003; Tirelli et al., 2003a), but may have a similar response to cocaine in both CPP and self-administration paradigms (Laviola et al., 1992; Frantz et al., 2007; Kantak et al., 2007). In contrast to these findings, we and others have reported that adolescent rodents are more sensitive to the primary rewarding effects of nicotine compared to adult rodents (Vastola et al., 2002; Belluzzi et al., 2004; Torrella et al., 2004; Shram et al., 2006; Brielmaier et al., 2007). This is significant in terms of the peak in acquisition of cigarette smoking during adolescence (11-13 years of age, Johnston et al., 2001; Johnston et al., 2006), particularly compared to the extremely low use rates of 200
other abused drugs during this period, e.g., cocaine, which peak later in young adulthood (e.g., 22.3 years of age, Johnson, 2001; Adlaf and Ialomiteanu, 2005). In addition to their blunted response to the rewarding effects of abused drugs, adolescents also appear to be insensitive to many of their aversive effects compared to adults; this has been reported for cocaine, amphetamine, alcohol as well as nicotine (Little et al., 1996; Adriani et al., 1998; Bolanos et al., 1998; Silveri and Spear, 1998; Collins and Izenwasser, 2002; White et al., 2002; Wilmouth and Spear, 2004; Shram et al., 2006). A blunted response to abused drugs may have important implications since reduced drug sensitivity may lead to increased use and produce a false sense of security in adolescents in that they believe they are less vulnerable to the addictive process.
SECTION 10 AGE DIFFERENCES IN FACTORS INFLUENCING MAINTENANCE OF NICOTINE TAKING SECTION 10.1 AGE DIFFERENCES IN NICOTINE WITHDRAWAL While the clinical literature indicates significant rates of nicotine dependence and withdrawal during adolescence (DiFranza et al., 2002; O'Loughlin et al., 2003; Gervais et al., 2006), the preclinical literature suggests a different story. We and others have not observed prominent physical or affective signs of mecamylamine-precipitated withdrawal in adolescent rodents chronically treated with nicotine, yet adult sensitivity to the aversive effects of withdrawal has been reliably demonstrated (O'Dell et al., 2006; Kota et al., 2007; O'Dell et al., 2007a; Shram et al., submitted). This developmental insensitivity to the affective and physical effects of nicotine withdrawal is maintained even when adolescent rats are exposed to much higher initial levels of nicotine compared to adult rats.
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In contrast to mecamylamine-precipitated withdrawal, spontaneous withdrawal from nicotine has had less consistent age-dependent effects. Physical signs during spontaneous withdrawal are more similar across age (Hamilton et al., 2006; Perry et al., 2006, but see Kota et al., 2007), but adolescent rats show greater cognitive impairments under these conditions (Wilmouth and Spear, 2006). These findings indicate that procedural differences are important to consider when interpreting results, yet also point to the idea that nicotine withdrawal may be qualitatively different in adolescence and adulthood. The qualitative age difference in nicotine withdrawal observed in rats is of interest and might be consistent with the clinical literature. Adolescent smokers are less successful using nicotine replacement therapy when quitting (Killen et al., 2001), indicating that physical dependence on nicotine may be less of a driving factor in the continued smoking during adolescence. Abstinent adolescent smokers however, appear particularly sensitive to the cognitive altering effects of withdrawal (Zack et al., 2001; Jacobsen et al., 2005; Jacobsen et al., 2007), although direct comparisons with adult smokers have not yet been reported. It is not surprising that adolescent nicotine dependence and withdrawal differ from that of adults, particularly when considering the motivating factors for smoking during adolescence. Environmental and peer influences play an integral role in the initiation and maintenance of smoking during adolescence, however adults are largely susceptible to genetic and individual factors, which would be more closely associated with physical dependence to nicotine (Han et al., 1999; McGue et al., 2000). Further, the expectancy of withdrawal effects, in addition to adolescent anhedonia, may also be contributing to the
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adolescent endorsement of nicotine dependence symptoms (Killen et al., 2001; Prokhorov et al., 2005).
SECTION 10.2 AGE DIFFERENCES IN NICOTINE WITHDRAWAL: POTENTIAL ROLE FOR REGION-DEPENDENT UPREGULATION OF NICOTINIC RECEPTORS The differences observed following mecamylamine-precipitated and spontaneous nicotine withdrawal suggest that procedural differences may be important in assessing withdrawal in the adolescent rat and that mecamylamine administration may be ineffective in producing withdrawal in adolescents. nAChRs in adolescent brain may have functionally distinct qualities that are constitutively present (Kota et al., 2007) or manifested following chronic exposure to nicotine. Since mecamylamine acts as a noncompetitive open channel blocker, it is possible that the nAChRs of adolescents may be in a protracted desensitized state, i.e., channel closed (due to immature recovery mechanism?), thereby preventing mecamylamine from binding appropriately. This possibility, while intriguing, remains to be tested empirically. The relative contribution of specific nAChR subtypes to nicotine withdrawal in adolescence is currently unknown. Therefore, it would also be of interest to investigate which nAChR subtypes are involved in adolescent nicotine withdrawal by using selective antagonists such as the α4 subunit selective antagonist, dihydro-beta-erythroidine (e.g., Watkins et al., 2000), and α7 subunit selective antagonist, methyllycaconitine (Nomikos et al., 1999, but see Markou and Paterson, 2001), which are thought to bind competitively to the nicotine recognition site of the nAChR (Williams and Robinson, 1984; Palma et al., 1996).
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There is evidence that nicotine exposure induces greater and more persistent nAChR upregulation in adolescent compared to adult hippocampus, cortex and midbrain (Trauth et al., 1999), yet the opposite has been observed in ventral and dorsal striatum (Collins et al., 2004). Interestingly, nicotine withdrawal is associated with both a decrease in DA release and an increase in ACh release in NAC, the latter of which has been demonstrated to modulate withdrawal effects (Rada et al., 2001). The greater ACh transmission in the striatum, combined with upregulated nAChRs, may therefore help explain the greater mecamylamine-precipitated withdrawal CPA in adult rats. Thus, the mecamylamine doses may in fact be sufficient to antagonize the nAChR in the adolescents, but the region-dependent response to chronic nicotine administration may influence the behavioural expression of withdrawal, e.g., upregulation in hippocampus and cortex and the cognitive disrupting effects in adolescent rats, and the upregulation in striatum and affective response to nicotine withdrawal in adult rats.
SECTION 10.3 AGE DIFFERENCES IN THE SUSCEPTIBILITY TO RELAPSE Early onset of smoking is associated with a reduced probability of quitting and increased likelihood of relapse (Chen and Millar, 1998; Cui et al., 2006), but such evidence has a number of confounds associated with it, e.g., self-selection, individual differences, history of exposure and self-report bias. For these reasons, we examined potential differences in the susceptibility to relapse in randomly selected rats that initiated selfadministration as adolescents or adults. Nicotine priming-induced reinstatement was independent of age at initiation of nicotine self-administration, whether testing occurred during or beyond the period of adolescence (Shram et al., 2007b,c). These findings indicate an age-independent susceptibility to the relapse-inducing effects of re-exposure to nicotine. 204
Other triggers of relapse, including stress and exposure to drug-associated cues may be of differential importance in relapse to smoking across development. Adolescents respond differently to stress compared to adults (Choi and Kellogg, 1996; Kabbaj et al., 2002; Romeo and McEwen, 2006). Maladaptive responses to stress include drug seeking, and thus, adolescents may rely on smoking as a coping strategy, particularly if they have not developed alternative strategies. Adolescents may also be differentially responsive to cues associated with smoking, e.g., friends who smoke. Therefore, it would be useful to examine cue and context-induced reinstatement of nicotine seeking. Overall, the results obtained from studies examining age differences in nicotine withdrawal and relapse fail to support the hypothesis that adolescents are more vulnerable to priming-induced relapse and the aversive effects of withdrawal that would contribute to the maintenance of nicotine taking.
SECTION 10.4 CONCLUSIONS AND LIMITATIONS The current evidence has provided a perplexing view upon the hypothesis of a biological susceptibility to nicotine addiction during adolescence. Based upon our experimental work, we suggest that adolescents are more susceptible to factors involved in the acquisition of nicotine taking, whereas adults may be more vulnerable to factors involved in the maintenance of nicotine taking. Adolescents are more sensitive to the rewarding effects of nicotine compared to adults, and are less sensitive to its aversive effects (Shram et al., 2006). The adolescent brain is also more responsive to nicotine within substrates implicated in drug reward (Shram et al., 2007a), indicating that the initial response to nicotine may be more positive in adolescents compared to adults. Therefore,
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these factors, in combination with powerful social influences, may account for the enhanced initiation rates of smoking during adolescence. The reduced sensitivity to the aversive effects of nicotine withdrawal in adolescence may also have important implications (Shram et al., submitted). While the lack of sensitivity may not impact continued use of nicotine via a negative reinforcement process (i.e., alleviation of withdrawal symptoms), the reduced aversiveness may instill a false sense of security from the addictive effects of nicotine. Adolescents may discount the possibility of becoming nicotine dependent because they do not experience the consequences of abstinence and believe that they can quit anytime, and therefore, continue to smoke. The lower BP achieved by adolescent rats self-administering nicotine (Shram et al., 2007b) may be indicative of developmental differences in the incentive motivation of nicotine rather than lower hedonic, or primary rewarding effects of nicotine during adolescence. Indeed, the majority of adolescent smokers does not smoke on a daily basis (Gervais et al., 2006; Karp et al., 2006) and also shows low elasticity in the motivation to obtain cigarettes (Ding, 2003). Therefore, adolescents may ‘like’ nicotine in that it is rewarding, but may ‘want’ it less, i.e., are less motivated to obtain it. In contrast to adolescents, adult rats are highly motivated to self-administer nicotine (Shram et al., 2007b) and are more sensitive to the aversive physical and affective effects of mecamylamine-precipitated nicotine withdrawal compared to adolescent rats administered similar or even higher amounts of nicotine (Shram et al., submitted). Although a direct comparison has yet to be made, the motivational drive of adult rats selfadministering nicotine may shift more rapidly compared to that of adolescent rats.
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Adolescent rats may self-administer more for the hedonic/pleasurable effects of nicotine, whereas adult rats may be more motivated to self-administer nicotine due to greater attribution of incentive salience and also possibly to alleviate the aversive effects of its removal. This would be supported by more persistent responding under PR and extinction conditions and the greater withdrawal effects in adult compared to adolescent rats (Shram et al., 2007b; Shram et al., submitted). Therefore, adult rats may become more responsive to factors involved in the maintenance of nicotine taking behaviour with repeated exposure to self-administered nicotine. Albeit sparse, there is evidence that adult rats can undergo spontaneous and mecamylamine-precipitated withdrawal under limited access self-administration conditions similar to those employed in the current series of experiments (1 hour/day, 7 days/week, Paterson and Markou, 2004). Therefore, the aversive effects of withdrawal may have been partly driving behavioural responding for nicotine in adult rats. Within the clinical literature, several reports indicate that adult smokers exhibit state-dependent changes in the motivation to work for cigarette puffs under PR conditions (Perkins et al., 1994; Willner et al., 1995; Rusted et al., 1998). PR responding correlates with the positive reinforcing effects of smoking in non-deprived subjects, whereas the negative reinforcing effects of smoking that alleviate craving correlated with responding under abstinence conditions (Willner et al., 1995). These studies indicate that adults are more motivated to obtain nicotine following a period of deprivation, which has also been observed in a rat model (O'Dell and Koob, 2007). These findings do not suggest however, greater sensitivity in adults since direct comparisons have not yet been made with adolescents.
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The epidemiological evidence indicates that early adolescent onset of smoking is associated with a reduced probability of quitting and increased risk of relapse compared to later onset of smoking (Breslau and Peterson, 1996; Chen and Millar, 1998; Cui et al., 2006). Therefore, in addition to a proximal susceptibility to the rewarding effects of nicotine during adolescence, early exposure to nicotine may have distinct persistent effects on later smoking behaviour. Due to several confounding factors, e.g., recall bias, selfselection, interpretation of these findings has been limited. However, in assessing the direct contribution of early compared to late nicotine exposure in a rat model, we and others have observed that adolescent, but not adult, exposure to nicotine (0.4 mg/kg/day x 10 days, s.c.) can facilitate subsequent nicotine self-administration in rats (Adriani et al., 2003; Appendix A). This appears to be due to changes in the reinforcing efficacy of nicotine since rats treated with nicotine during adolescence achieve higher BP compared to their vehicletreated counterparts, whereas similar nicotine treatment in adulthood does not significantly affect subsequent BP. Therefore, even low level exposure to nicotine during adolescence can dramatically alter subsequent nicotine taking behaviour, further strengthening the idea that adolescents exhibit a unique biological susceptibility to nicotine. Using a rat model, in which factors such as peer pressure and self-selection could be excluded, we have observed that adolescents are more responsive to the acute rewarding effects of nicotine, but that adults are more susceptible to the incentive motivational effects of nicotine and the aversive effects of withdrawal. That being said however, although adolescents may be less motivated to obtain nicotine, the early intermittent exposure to nicotine can have distinct, significant long-term effects on drug taking behaviours.
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Our assessment of age differences in the processes involved in the acquisition and maintenance of nicotine taking generated a number of interesting and novel findings that, at times, contradicted the epidemiological evidence upon which our hypotheses were based. We acknowledge that the model we used has its limitations. Our experimental work was based upon the assumption that smoking is largely driven by the reinforcing and addictive actions of nicotine (Henningfield and Goldberg, 1983; Harvey et al., 2004). While nicotine has significant psychoactive properties and has been shown to be important in maintaining smoking behaviours, there are approximately 4 000 non-nicotine constituents of tobacco (U.S. Surgeon General's report, 1989). A number of these have pharmacological activities of their own, e.g, carbon monoxide, acetaldehyde, monoamine oxidase inhibitors such as 2,3,6-trimethyl-1,4-naphthoquinone, or can modulate smoking behaviour, e.g., tar, but were not accounted for in the current work. To date, there is scant evidence indicating that nicotine mediates the reinforcing action of tobacco smoke in adolescents. Recently, Kassel and colleagues (2007b) have demonstrated that adolescents titrate their smoking by taking more puffs when smoking a denicotinized compared to a high nicotine yield cigarette. Although this contrasts evidence from adult smokers who modify their smoking topography by taking longer puffs from denicotinized cigarettes, this study indicates that adolescents are seeking nicotine from smoking cigarettes. Motives for smoking may also differ across development. Adolescents may smoke primarily for the pleasurable effects of smoking or for other reasons, e.g. affect regulation. A recent report suggests that adolescents may smoke to reduce negative affect, an effect influenced by level of dependence and craving (Kassel et al., 2007a). The observations made were partly dependent upon the nicotine content of the cigarette, although
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expectancies, placebo effect and role of non-nicotine tobacco constituents may also be important in modifying negative affect during a smoking bout in adolescence. Instrumental use of cigarette smoking could also contribute to acquisition of smoking during adolescence, independent of the reinforcing action of nicotine. For example, adolescents (< 17 years) are almost twice as likely to smoke if diagnosed with ADHD (Lambert and Hartsough, 1998), and may do so as self-medication. A recent study of non-smokers diagnosed with ADHD demonstrated that nicotine, delivered via transdermal patch, improved inhibitory processes and also reduced anxiety and irritability (Potter and Newhouse, 2004). This evidence suggests that perhaps adolescent smokers with ADHD smoke to alleviate their symptoms, and that nicotine is playing a significant role in this process. We do not yet know if adolescents are smoking to obtain nicotine or for the other pharmacologically active constituents, but based upon the available data, nicotine does modify their smoking behaviour, suggesting it is involved in the acquisition and maintenance of adolescent smoking.
SECTION 10.5 FUTURE WORK A number of questions have arisen from the experimental work presented here and elsewhere regarding the short and long-term effects of adolescent nicotine exposure. In the current work, we observed that adolescent rats are more sensitive to the rewarding effects of nicotine, yet exhibit reduced motivation to self-administer it. Although not specifically presented here, even low level exposure to nicotine during adolescence has a significant and unique effect upon subsequent (adult) nicotine taking behaviour (Appendix A; also see Adriani et al., 2003). These findings have identified several issues that would be important
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to address to gain a greater understanding of a biological susceptibility to nicotine during adolescence.
Section 10.5.1. Age differences in the motivation to self-administer nicotine: Role for dopamine We raised the possibility that the reduced motivation of adolescent rats to selfadminister nicotine may be related to immature DA function (Section 9.2). There are a variety of approaches to assess potential age differences in the motivation to selfadministration nicotine and the role DA might play. First, higher doses of nicotine, which would produce greater DA release in NAC (Mifsud et al., 1989), may be more reinforcing in adolescent rats, as has previously been observed in adult rats (Donny et al., 1999). More nicotine is required to stimulate DA release in adolescent compared to adult rat brain, but when this threshold is achieved, the amount of DA released is greater in younger rats (Azam et al., 2007). Therefore, this increased DA release may result in greater motivation to self-administer nicotine, i.e., greater reinforcing efficacy of nicotine, in adolescents compared to adults at higher infusion doses. Considering this possibility, a full doseresponse under PR testing conditions would likely address this issue. Second, it would also be useful to compare the reinforcing efficacy of cocaine across age, which appears to increase DA release similarly in adolescents and adults (Frantz et al., 2007). This would be important to determine if adolescents are willing to work as hard as adults, or at least more than for nicotine, for this potent psychostimulant. It could also rule out age differences in performance, an issue that was not fully addressed with the non-drug reinforcer, saccharin, due to low BP in both age groups. Kantak et al. (2007) recently reported that adolescent and adult rats respond similarly for cocaine under a 211
number of reinforcement schedules, including FR5, indicating that adolescents are equally capable of responding for stimuli under higher reinforcement schedules. It is tempting to suggest that because the DA transporter (to which cocaine binds) reaches maturity during early adolescence (Tarazi et al., 1998b; Collins and Izenwasser, 2002), sufficient DA remains in the synaptic cleft to maintain self-administration of cocaine under higher response costs in adolescents. Third, to directly test the hypothesis that adolescent rats are less motivated to selfadminister nicotine due to immature DA function, a series of experiments could examine the effect of NAC DA lesions on behavioural responding. If NAC DA is principally involved in the incentive motivational effects of stimuli (Aberman and Salamone, 1999) rather than their primary rewarding or hedonic effects (Berridge, 1996; Berridge and Robinson, 2003), NAC DA lesions would not be expected to affect nicotine selfadministration under a FR1 reinforcement schedule, but would selectively impair responding under a PR reinforcement schedule. We might also anticipate a more marked lesion effect in adult rats since their age-appropriate sham controls would still have an intact, fully mature DA system. As a complementary set of studies, the role of DA on nicotine-motivated responding could also be investigated pharmacologically through administration of DA agonists and antagonists, which would be expected to increase and decrease responding under PR conditions, respectively, without significantly altering FR1 responding.
Section 10.5.2. Interactions between stress and nicotine during adolescence A second important issue to address is the potential interaction between stress and age upon the response to nicotine. Adolescence has been referred to as a time of ‘storm and 212
stress’ (see Spear, 2000, p. 428) and could be a particularly sensitive developmental period to interactions between stress and nicotine. Stress (and its related hormones and neurotransmitters) may be an important contributor to the acquisition of nicotine taking during adolescence by altering the reinforcing effects of nicotine, as it does with cocaine (Goeders and Guerin, 1996; Goeders, 2002). Nicotine stimulates the HPA axis and its related NE circuitry of adult rodents (Matta et al., 1998) and humans (Wilkins et al., 1982), however we do not yet understand nicotine’s effects upon these systems in the adolescent and the associated implications. As previously mentioned, nicotine’s effects on CORT release may be important in modulating its reinforcing effects, similar to that observed with cocaine (Goeders, 2002). Although acute nicotine administration does not significantly increase CORT levels in juvenile mice (Cao et al., 2007), it is possible that under conditions of stress, during which time the adolescent CORT response is prolonged compared to that of adults (Romeo and McEwen, 2006), nicotine may become even more reinforcing in adolescents compared to adults. Therefore, stress-induced increases in CORT during adolescence could further contribute to enhanced acquisition of nicotine taking by altering the motivational effects of nicotine. To test the hypothesis that age and stress interact with the reinforcing effects of nicotine, one could apply a variety of stressors (e.g., pharmacological, social, physical) to both adolescent and adult rats and examine subsequent behavioural (e.g., CPP, selfadministration) and physiological (e.g., CORT, NE) responses to nicotine. The effects of acute (Ramsey and Van Ree, 1993) and repeated (Mantsch and Katz, 2007) physical stress can have a differential impact upon self-administration behaviour in adult rats, and
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therefore, a direct comparison across age could provide further insight into the impact of prolonged stress on the response to nicotine during adolescence.
Section 10.5.3. Long-term effects of nicotine on HPA axis and NE function: Subsequent responses to nicotine Nicotine preferentially increases CORT levels of adult compared to juvenile mice (Cao et al., 2007), but repeated nicotine administration during adolescence may have distinct long-term effects upon subsequent HPA axis and NE responses to nicotine that might influence later drug taking behaviour. Trauth and colleagues (2001) have demonstrated that chronic nicotine administration during adolescence blunts the subsequent NE response to an acute nicotine challenge. More recently, we have observed attenuated reinstatement of nicotine seeking induced by yohimbine, an α2-adrenoceptor antagonist commonly used as a pharmacological stressor (e.g., Shepard et al., 2004; Le et al., 2005; Fletcher et al., 2007), in rats that initiated nicotine self-administration during adolescence compared to those that initiated during adulthood (Shram et al., unpublished observations). These data suggest that the NE system may be sensitive to nicotine exposure during adolescence and that the effects are long lasting. Such a potential alteration in NE function may also have a long-term effect on the reinforcing effects of drugs of abuse. Although DA is traditionally implicated in reward and motivation, NE also plays a modulatory role in the addiction process. For example, when NE is blocked chronically, DA release is attenuated but accompanied by a compensatory increase in high affinity DA receptors, resulting in a hypersensitivity to drugs of abuse, i.e., psychostimulants (Weinshenker and Schroeder, 2007). If the NE system is blunted by early exposure to nicotine, this might explain the greater reinforcing 214
efficacy of nicotine under self-administration conditions in rats treated with nicotine during adolescence (Appendix A; also see Adriani et al., 2003). To test the hypothesis of a unique long-term effect of adolescent nicotine exposure upon stress-related circuitry (i.e., the HPA axis and NE system), one would first pretreat adolescent and adult rats with nicotine. Nicotine exposure via chronic infusion and intermittent injections should also be compared to investigate the effects of timing and duration in addition to overall exposure, since adolescents do not smoke on a daily basis (Gervais et al., 2006). Following an intervening period, the CORT response as well as elevations in NE following nicotine administration could be examined under both passive and self-administration conditions, which are known to produce different neurochemical responses (Donny et al., 2000). Such evidence would provide valuable insight into: 1) the interactions between stress and age upon the behavioural response to nicotine and 2) the neurobiological mechanisms underlying the greater persistence of smoking behaviour in individuals who initiated during adolescence.
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REFERENCES Aberman J. E., Salamone J. D. (1999) Nucleus accumbens dopamine depletions make rats more sensitive to high ratio requirements but do not impair primary food reinforcement. Neuroscience 92:545-552. Aceto M. D., Scates S. M., Lowe J. A., Martin B. R. (1996) Dependence on delta 9tetrahydrocannabinol: studies on precipitated and abrupt withdrawal. J Pharmacol Exp Ther 278:1290-1295. Acheson S. K., Richardson R., Swartzwelder H. S. (1999) Developmental changes in seizure susceptibility during ethanol withdrawal. Alcohol 18:23-26. Acquas E., Carboni E., Leone P., Di Chiara G. (1989) SCH 23390 blocks drug-conditioned place-preference and place-aversion: anhedonia (lack of reward) or apathy (lack of motivation) after dopamine-receptor blockade? Psychopharmacology 99:151-155. Adlaf E.M., Ialomiteanu A. (2005) Other drug use and problems. In: Canadian Addiction Survey, pp 55-70. Adriani W., Laviola G. (2000) A unique hormonal and behavioral hyporesponsivity to both forced novelty and d-amphetamine in periadolescent mice. Neuropharmacology 39:334-346. Adriani W., Laviola G. (2003) Elevated levels of impulsivity and reduced place conditioning with d-amphetamine: two behavioral features of adolescence in mice. Behav Neurosci 117:695-703. Adriani W., Chiarotti F., Laviola G. (1998) Elevated novelty seeking and peculiar damphetamine sensitization in periadolescent mice compared with adult mice. Behav Neurosci 112:1152-1166. Adriani W., Macri S., Pacifici R., Laviola G. (2002) Peculiar vulnerability to nicotine oral self-administration in mice during early adolescence. Neuropsychopharmacology 27:212-224. Adriani W., Spijker S., Deroche-Gamonet V., Laviola G., Le Moal M., Smit A.B., Piazza P.V. (2003) Evidence for enhanced vulnerability to nicotine during periadolescence in rats. J Neurosci 23:4712-4716. Agrawal A., Grant J. D., Waldron M., Duncan A. E., Scherrer J. F., Lynskey M. T., Madden P. A., Bucholz K. K., Heath A. C. (2006) Risk for initiation of substance use as a function of age of onset of cigarette, alcohol and cannabis use: Findings in a Midwestern female twin cohort. Prev Med 435:125-128. Alfoldi P., Tobler I., Borbely A. A. (1990) Sleep regulation in rats during early development. Am J Physiol 258:R634-644. Alheid G. F. (2003) Extended amygdala and basal forebrain. Ann N Y Acad Sci 985:185205. Andersen S. L., LeBlanc C. J., Lyss P. J. (2001) Maturational increases in c-fos expression in the ascending dopamine systems. Synapse 41:345-350. Andersen S. L., Arvanitogiannis A., Pliakas A. M., LeBlanc C., Carlezon W. A., Jr. (2002) Altered responsiveness to cocaine in rats exposed to methylphenidate during development. Nat Neurosci 5:13-14. Andreoli M., Tessari M., Pilla M., Valerio E., Hagan J. J., Heidbreder C. A. (2003) Selective antagonism at dopamine D3 receptors prevents nicotine-triggered relapse to nicotine-seeking behavior. Neuropsychopharmacology 28:1272-1280. 216
Anokhin A. P., Birbaumer N., Lutzenberger W., Nikolaev A., Vogel F. (1996) Age increases brain complexity. Electroencephalogr Clin Neurophysiol 99:63-68. Arnett J. (1992) Reckless behavior in adolescence: A developmental perspective. Developmental Review 12:339-373. Arnold J. M., Roberts D. C. (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441-447. Arnsten A. F., Li B. M. (2005) Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 57:1377-1384. Audrain-McGovern J., Al Koudsi N., Rodriguez D., Wileyto E. P., Shields P. G., Tyndale R. F. (2007) The role of CYP2A6 in the emergence of nicotine dependence in adolescents. Pediatrics 119:e264-274. Avenevoli S., Merikangas K. R. (2003) Familial influences on adolescent smoking. Addiction 98 Suppl 1:1-20. Azam L., Chen Y., Leslie F. M. (2007) Developmental regulation of nicotinic acetylcholine receptors within midbrain dopamine neurons. Neuroscience 144:1347-1360. Badanich K. A., Kirstein C. L. (2004) Nicotine administration significantly alters accumbal dopamine in the adult but not in the adolescent rat. Ann N Y Acad Sci 1021:410417. Badanich K. A., Adler K. J., Kirstein C. L. (2006) Adolescents differ from adults in cocaine conditioned place preference and cocaine-induced dopamine in the nucleus accumbens septi. Eur J Pharmacol 550:95-106. Baker T. B., Brandon T. H., Chassin L. (2004a) Motivational influences on cigarette smoking. Annu Rev Psychol 55:463-491. Baker T. B., Piper M. E., McCarthy D. E., Majeskie M. R., Fiore M. C. (2004b) Addiction motivation reformulated: an affective processing model of negative reinforcement. Psychol Rev 111:33-51. Balfour D. J., Khullar A. K., Longden A. (1975) Effects of nicotine on plasma corticosterone and brain amines in stressed and unstressed rats. Pharmacol Biochem Behav 3:179-184. Bardo M. T., Neisewander J. L. (1986) Single-trial conditioned place preference using intravenous morphine. Pharmacol Biochem Behav 25:1101-1105. Bardo M. T., Bevins R. A. (2000) Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl) 153:31-43. Bardo M. T., Valone J. M., Bevins R. A. (1999a) Locomotion and conditioned place preference produced by acute intravenous amphetamine: role of dopamine receptors and individual differences in amphetamine self-administration. Psychopharmacology (Berl) 143:39-46. Bardo M. T., Green T. A., Crooks P. A., Dwoskin L. P. (1999b) Nornicotine is selfadministered intravenously by rats. Psychopharmacology (Berl) 146:290-296. Barr C. S., Schwandt M. L., Newman T. K., Higley J. D. (2004) The use of adolescent nonhuman primates to model human alcohol intake: neurobiological, genetic, and psychological variables. Ann N Y Acad Sci 1021:221-233. Bauer R.H., Duncan D.L. (1975) Differential effects of d-amphetamine in mature and immature rats. Physiological Psychology 3:312-316.
217
Bechara A., Nader K., van der Kooy D. (1998) A two-separate-motivational-systems hypothesis of opioid addiction. Pharmacol Biochem Behav 59:1-17. Bechara A., Damasio H., Damasio A. R., Lee G. P. (1999) Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making. J Neurosci 19:5473-5481. Belluzzi J. D., Wang R., Leslie F. M. (2005) Acetaldehyde enhances acquisition of nicotine self-administration in adolescent rats. Neuropsychopharmacology 30:705-712. Belluzzi J. D., Lee A. G., Oliff H. S., Leslie F. M. (2004) Age-dependent effects of nicotine on locomotor activity and conditioned place preference in rats. Psychopharmacology (Berl) 174:389-395. Benes F. M., Taylor J. B., Cunningham M. C. (2000) Convergence and plasticity of monoaminergic systems in the medial prefrontal cortex during the postnatal period: implications for the development of psychopathology. Cereb Cortex 10:1014-1027. Benowitz N. L. (1996) Pharmacology of nicotine: addiction and therapeutics. Annu Rev Pharmacol Toxicol 36:597-613. Benowitz N. L., Jacob P., 3rd (1993) Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers. Clin Pharmacol Ther 53:316-323. Benowitz N. L., Hall S. M., Herning R. I., Jacob P., 3rd, Jones R. T., Osman A. L. (1983) Smokers of low-yield cigarettes do not consume less nicotine. N Engl J Med 309:139-142. Berrendero F., Mendizabal V., Robledo P., Galeote L., Bilkei-Gorzo A., Zimmer A., Maldonado R. (2005) Nicotine-induced antinociception, rewarding effects, and physical dependence are decreased in mice lacking the preproenkephalin gene. J Neurosci 25:1103-1112. Berridge K. C. (1996) Food reward: brain substrates of wanting and liking. Neurosci Biobehav Rev 20:1-25. Berridge K. C., Robinson T. E. (2003) Parsing reward. Trends Neurosci 26:507-513. Bevins R. A., Besheer J. (2001) Individual differences in rat locomotor activity are diminished by nicotine through stimulation of central nicotinic acetylcholine receptors. Physiol Behav 72:237-244. Biala G., Budzynska B. (2006) Reinstatement of nicotine-conditioned place preference by drug priming: effects of calcium channel antagonists. Eur J Pharmacol 537:85-93. Blaha C.D., Allen L. F., Das S., Inglis W.L., Latimer M. P., Vincent S.R., Winn P. (1996) Modulation of dopamine efflux in the nucleus accumbens after cholinergic stimulation of the ventral tegmental area in intact, pedunculopontine tegmental nucleus-lesioned, and laterodorsal tegmental nucleus-lesioned rats. J Neurosci 16:714-722. Blokhina E. A., Kashkin V. A., Zvartau E. E., Danysz W., Bespalov A. Y. (2005) Effects of nicotinic and NMDA receptor channel blockers on intravenous cocaine and nicotine self-administration in mice. Eur Neuropsychopharmacol 15:219-225. Bock J., Braun K. (1999) Blockade of N-methyl-D-aspartate receptor activation suppresses learning-induced synaptic elimination. Proc Natl Acad Sci U S A 96:2485-2490. Bogin B. (1999a) Evolutionary perspective on human growth. Annual Review of Anthropology 28:109-153. Bogin B. (1999b) Patterns of human growth, 2nd Edition. New York: Cambridge University Press. 218
Bolanos C. A., Glatt S. J., Jackson D. (1998) Subsensitivity to dopaminergic drugs in periadolescent rats: a behavioral and neurochemical analysis. Brain Res Dev Brain Res 111:25-33. Bolanos C. A., Garmsen G. M., Clair M. A., McDougall S. A. (1996) Effects of the kappaopioid receptor agonist U-50,488 on morphine-induced place preference conditioning in the developing rat. Eur J Pharmacol 317:1-8. Bond N., Di Giusto E. (1975) Amount of solution drunk is a factor in the establishment of taste aversion. Animal Learning and Behavior 3:81-84. Boomsma D. I., Koopmans J. R., Van Doornen L. J., Orlebeke J. F. (1994) Genetic and social influences on starting to smoke: a study of Dutch adolescent twins and their parents. Addiction 89:219-226. Botvin G. J., Baker E., Goldberg C. J., Dusenbury L., Botvin E. M. (1992) Correlates and predictors of smoking among black adolescents. Addict Behav 17:97-103. Bozarth M. A. (1990) Drug addiction as a psychobiological process. In: Addiction controversies (Warburton DM, ed), pp 112-134. London: Harwood Academic Publishers. Bozarth M.A. (1987) Conditioned place preference: A parametric analysis using systemic heroin injections. In: Methods of assessing the reinforcing properties of abused drugs (Bozarth MA, ed), pp 241-273. New York: Springer-Verlag. Brandon C. L., Marinelli M., Baker L. K., White F. J. (2001) Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats. Neuropsychopharmacology 25:651-661. Breslau N., Peterson E. L. (1996) Smoking cessation in young adults: age at initiation of cigarette smoking and other suspected influences. Am J Public Health 86:214-220. Brielmaier J. M., McDonald C. G., Smith R. F. (2007) Immediate and long-term behavioral effects of a single nicotine injection in adolescent and adult rats. Neurotoxicol Teratol 29:74-80. Brioni J. D., O'Neill A. B., Kim D. J., Buckley M. J., Decker M. W., Arneric S. P. (1994) Anxiolytic-like effects of the novel cholinergic channel activator ABT-418. J Pharmacol Exp Ther 271:353-361. Bronstein P. M., Spear N. E. (1972) Acquisition of a spatial discrimination by rats as a function of age. J Comp Physiol Psychol 78:208-212. Brunell S. C., Spear L. P. (2005) Effect of stress on the voluntary intake of a sweetened ethanol solution in pair-housed adolescent and adult rats. Alcohol Clin Exp Res 29:1641-1653. Buczek Y., Le A. D., Wang A., Stewart J., Shaham Y. (1999) Stress reinstates nicotine seeking but not sucrose solution seeking in rats. Psychopharmacology (Berl) 144:183-188. Burt R. D., Peterson A. V., Jr. (1998) Smoking cessation among high school seniors. Prev Med 27:319-327. Byrnes J. P. (2002) The development of decision-making. J Adolesc Health 31:208-215. Caggiula A. R., Donny E. C., White A. R., Chaudhri N., Booth S., Gharib M. A., Hoffman A., Perkins K. A., Sved A. F. (2001) Cue dependency of nicotine selfadministration and smoking. Pharmacol Biochem Behav 70:515-530.
219
Caggiula A. R., Donny E. C., White A. R., Chaudhri N., Booth S., Gharib M. A., Hoffman A., Perkins K. A., Sved A. F. (2002) Environmental stimuli promote the acquisition of nicotine self-administration in rats. Psychopharmacology (Berl) 163:230-237. Caine S.B., Lintz R., Koob G. F. (1993) Intravenous drug self-administration techniques in animals. In: Behavioural Neuroscience: A Practical Approach (Sahgal A, ed), pp 117-143. New York: Oxford University Press. Calcagnetti D. J., Schechter M. D. (1994) Nicotine place preference using the biased method of conditioning. Prog Neuropsychopharmacol Biol Psychiatry 18:925-933. Cameron J.L. (1990) Factors controlling the onset of puberty in primates. In: Adolescence and Puberty. The Kinsey Institute Series (Bancroft J, Reinisch JM, eds). New York: Oxford University Press. Campbell A., Baldessarini R. J., Teicher M. H. (1988) Decreasing sensitivity to neuroleptic agents in developing rats; evidence for a pharmacodynamic factor. Psychopharmacology (Berl) 94:46-51. Campbell B. A., Lytle L. D., Fibiger H. C. (1969) Ontogeny of adrenergic arousal and cholinergic inhibitory mechanisms in the rat. Science 166:635-637. Campbell B. A., Misanin J.R., White B.C., Lytle L. D. (1974) Species differences in ontogeny on memory: Indirect support for neural mediation as a determinant of forgetting. J Comp Physiol Psychol 8:193-202. Campbell J. O., Wood R. D., Spear L. P. (2000) Cocaine and morphine-induced place conditioning in adolescent and adult rats. Physiol Behav 68:487-493. Cao J., Belluzzi J. D., Loughlin S. E., Keyler D. E., Pentel P. R., Leslie F. M. (2007) Acetaldehyde, a Major Constituent of Tobacco Smoke, Enhances Behavioral, Endocrine, and Neuronal Responses to Nicotine in Adolescent and Adult Rats. Neuropsychopharmacology 32:2025-2035. Caraballo R. S., Yee S. L., Gfroerer J. C., Pechacek T. F., Henson R. (2006) Tobacco use among racial and ethnic population subgroups of adolescents in the United States. Prev Chronic Dis 3:A39. Carboni E., Acquas E., Leone P., Di Chiara G. (1989) 5HT3 receptor antagonists block morphine- and nicotine- but not amphetamine-induced reward. Psychopharmacology 97:175-178. Carboni E., Bortone L., Giua C., Di Chiara G. (2000a) Dissociation of physical abstinence signs from changes in extracellular dopamine in the nucleus accumbens and in the prefrontal cortex of nicotine dependent rats. Drug Alcohol Depend 58:93-102. Carboni E., Silvagni A., Rolando M. T., Di Chiara G. (2000b) Stimulation of in vivo dopamine transmission in the bed nucleus of stria terminalis by reinforcing drugs. J Neurosci 20:RC102. Carr G. D., White N. M. (1983) Conditioned place preference from intra-accumbens but not intra-caudate amphetamine injections. Life Sci 33:2551-2557. Carr G. D., White N. M. (1986) Anatomical disassociation of amphetamine's rewarding and aversive effects: an intracranial microinjection study. Psychopharmacology (Berl) 89:340-346. Carskadon M. A., Vieira C., Acebo C. (1993) Association between puberty and delayed phase preference. Sleep 16:258-262.
220
Castane A., Valjent E., Ledent C., Parmentier M., Maldonado R., Valverde O. (2002) Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology 43:857-867. Caster J. M., Walker Q. D., Kuhn C. M. (2005) Enhanced behavioral response to repeateddose cocaine in adolescent rats. Psychopharmacology (Berl) 183:218-225. Castrucci B. C., Gerlach K. K., Kaufman N. J., Orleans C. T. (2002) Adolescents' acquisition of cigarettes through noncommercial sources. J Adolesc Health 31:322326. Centers for Disease Control and Prevention (1996) Projected smoking-related deaths among youth - United States. Morbidity and Mortality Weekly Report 45:971-974. Centers for Disease Control and Prevention (2005) Annual smoking-attributable mortality, years of potential life lost, and productivity losses - United States, 1997-2001. In: Morbidity and Mortality Weekly Report, pp 625-628. Centers for Disease Control and Prevention (2006a) Cigarette use among high school students - United States, 1991-2005. Morbidity and Mortality Weekly Report 55:724-726. Centers for Disease Control and Prevention (2006b) Use of cigarettes and other tobacco products among students aged 13-15 years - worldwide, 1999-2005. Morbidity and Mortality Weekly Report 55:553-556. Chambers R. A., Potenza M. N. (2003) Neurodevelopment, impulsivity, and adolescent gambling. J Gambl Stud 19:53-84. Chambers R. A., Taylor J. R., Potenza M. N. (2003) Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry 160:1041-1052. Chambers R. A., Moore J., McEvoy J. P., Levin E. D. (1996) Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia. Neuropsychopharmacology 15:587-594. Chassin L., Presson C. C., Sherman S. J. (1984) Cognitive and social influence factors in adolescent smoking cessation. Addict Behav 9:383-390. Chaudhri N., Caggiula A. R., Donny E. C., Booth S., Gharib M. A., Craven L. A., Allen S. S., Sved A. F., Perkins K. A. (2005) Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats. Psychopharmacology (Berl) 180:258-266. Cheeta S., Irvine E. E., Tucci S., Sandhu J., File S. E. (2001) In adolescence, female rats are more sensitive to the anxiolytic effect of nicotine than are male rats. Neuropsychopharmacology 25:601-607. Chen H., Matta S. G., Sharp B. M. (2007) Acquisition of nicotine self-administration in adolescent rats given prolonged access to the drug. Neuropsychopharmacology 32:700-709. Chen J., Millar W. J. (1998) Age of smoking initiation: implications for quitting. Health Rep 9:39-46(Eng); 39-48(Fre). Chester J. A., Cunningham C. L. (1999) GABA(A) receptors modulate ethanol-induced conditioned place preference and taste aversion in mice. Psychopharmacology (Berl) 144:363-372.
221
Chiamulera C., Borgo C., Falchetto S., Valerio E., Tessari M. (1996) Nicotine reinstatement of nicotine self-administration after long-term extinction. Psychopharmacology (Berl) 127:102-107. Childress A. R., Hole A. V., Ehrman R. N., Robbins S. J., McLellan A. T., O'Brien C. P. (1993) Cue reactivity and cue reactivity interventions in drug dependence. NIDA Res Monogr 137:73-95. Childress A. R., Mozley P. D., McElgin W., Fitzgerald J., Reivich M., O'Brien C. P. (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:11-18. Choi S., Kellogg C. K. (1992) Norepinephrine utilization in the hypothalamus of the male rat during adolescent development. Dev Neurosci 14:369-376. Choi S., Kellogg C. K. (1996) Adolescent development influences functional responsiveness of noradrenergic projections to the hypothalamus in male rats. Brain Res Dev Brain Res 94:144-151. Choi S., Weisberg S. N., Kellogg C. K. (1997) Control of endogenous norepinephrine release in the hypothalamus of male rats changes over adolescent development. Brain Res Dev Brain Res 98:134-141. Clark D. B., Kirisci L., Moss H. B. (1998a) Early adolescent gateway drug use in sons of fathers with substance use disorders. Addict Behav 23:561-566. Clark D. B., Kirisci L., Tarter R. E. (1998b) Adolescent versus adult onset and the development of substance use disorders in males. Drug Alcohol Depend 49:115121. Clark P. I., Schooley M. W., Pierce B., Schulman J., Hartman A. M., Schmitt C. L. (2006) Impact of home smoking rules on smoking patterns among adolescents and young adults. Prev Chronic Dis 3:A41. Clarke P. B., Kumar R. (1983) The effects of nicotine on locomotor activity in non-tolerant and tolerant rats. Br J Pharmacol 78:329-337. Clarke P. B., Fibiger H. C. (1987) Apparent absence of nicotine-induced conditioned place preference in rats. Psychopharmacology (Berl) 92:84-88. Cohen C., Welzl H., Battig K. (1991) Effects of nicotine, caffeine, and their combination on locomotor activity in rats. Pharmacol Biochem Behav 40:121-123. Colby S. M., Tiffany S. T., Shiffman S., Niaura R. S. (2000) Are adolescent smokers dependent on nicotine? A review of the evidence. Drug Alcohol Depend 59 Suppl 1:S83-95. Collins S. L., Izenwasser S. (2002) Cocaine differentially alters behavior and neurochemistry in periadolescent versus adult rats. Brain Res Dev Brain Res 138:27-34. Collins S. L., Wade D., Ledon J., Izenwasser S. (2004) Neurochemical alterations produced by daily nicotine exposure in periadolescent vs. adult male rats. Eur J Pharmacol 502:75-85. Compas B. E., Orosan P. G., Grant K. E. (1993) Adolescent stress and coping: implications for psychopathology during adolescence. J Adolesc 16:331-349. Compas B. E., Connor-Smith J. K., Saltzman H., Thomsen A. H., Wadsworth M. E. (2001) Coping with stress during childhood and adolescence: problems, progress, and potential in theory and research. Psychol Bull 127:87-127. Compechot C., Baulieu E., Robel P. (1981) Testosterone, dihydrotestosterone
222
and andresanediols in plasma testis and prostrates of rats during development. Acta Endocrinol 96:127-135. Conklin H. M., Luciana M., Hooper C. J., Yarger R. S. (2007) Working memory performance in typically developing children and adolescents: behavioral evidence of protracted frontal lobe development. Dev Neuropsychol 31:103-128. Conrad K. M., Flay B. R., Hill D. (1992) Why children start smoking cigarettes: predictors of onset. Br J Addict 87:1711-1724. Coogan P. F., Adams M., Geller A. C., Brooks D., Miller D. R., Lew R. A., Koh H. K. (1998) Factors associated with smoking among children and adolescents in Connecticut. Am J Prev Med 15:17-24. Corrigall W. A. (1999) Nicotine self-administration in animals as a dependence model. Nicotine Tob Res 1:11-20. Corrigall W. A., Coen K. M. (1989) Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology (Berl) 99:473-478. Corrigall W. A., Coen K. M. (1991) Selective dopamine antagonists reduce nicotine selfadministration. Psychopharmacology 104:171-176. Corrigall W. A., Coen K. M. (1994) Nicotine self-administration and locomotor activity are not modified by the 5-HT3 antagonists ICS 205-930 and MDL 72222. Pharmacol Biochem Behav 49:67-71. Corrigall W. A., Coen K. M., Adamson K. L. (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278-284. Corrigall W. A., Franklin K. B., Coen K. M., Clarke P. B. (1992) The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology 107:285-289. Corrigall W. A., Coen K. M., Zhang J., Adamson K. L. (2001) GABA mechanisms in the pedunculopontine tegmental nucleus influence particular aspects of nicotine selfadministration selectively in the rat. Psychopharmacology (Berl) 158:190-197. Corrigall W. A., Coen K. M., Adamson K. L., Chow B. L., Zhang J. (2000) Response of nicotine self-administration in the rat to manipulations of mu-opioid and gammaaminobutyric acid receptors in the ventral tegmental area. Psychopharmacology (Berl) 149:107-114. Coulter C. L., Happe H. K., Murrin L. C. (1996) Postnatal development of the dopamine transporter: a quantitative autoradiographic study. Brain Res Dev Brain Res 92:172181. Crawford A. M., Pentz M. A., Chou C. P., Li C., Dwyer J. H. (2003) Parallel developmental trajectories of sensation seeking and regular substance use in adolescents. Psychol Addict Behav 17:179-192. Crooks P. A., Li M., Dwoskin L. P. (1997) Metabolites of nicotine in rat brain after peripheral nicotine administration. Cotinine, nornicotine, and norcotinine. Drug Metab Dispos 25:47-54. Cruz F. C., Delucia R., Planeta C. S. (2005) Differential behavioral and neuroendocrine effects of repeated nicotine in adolescent and adult rats. Pharmacol Biochem Behav 80:411-417. Csikszentmihalyi M., Larson R., Prescott S. (1971) The ecology of adolescent activity and experience. Journal of Youth and Adolescence 6:281-294. 223
Cui Y., Wen W., Moriarty C. J., Levine R. S. (2006) Risk factors and their effects on the dynamic process of smoking relapse among veteran smokers. Behav Res Ther 44:967-981. Cunningham C. L., Fidler T. L., Hill K. G. (2000) Animal models of alcohol's motivational effects. Alcohol Res Health 24:85-92. Cunningham C. L., Ferree N. K., Howard M. A. (2003) Apparatus bias and place conditioning with ethanol in mice. Psychopharmacology (Berl) 170:409-422. Cunningham M. G., Connor C. M., Zhang K., Benes F. M. (2005) Diminished serotonergic innervation of adult medial prefrontal cortex after 6-OHDA lesions in the newborn rat. Brain Res Dev Brain Res 157:124-131. Curran T., Morgan J. I. (1995) Fos: an immediate-early transcription factor in neurons. J Neurobiol 26:403-412. Cutler G. B., Jr., Glenn M., Bush M., Hodgen G. D., Graham C. E., Loriaux D. L. (1978) Adrenarche: a survey of rodents, domestic animals, and primates. Endocrinology 103:2112-2118. Dalton M. A., Sargent J. D., Beach M. L., Bernhardt A. M., Stevens M. (1999) Positive and negative outcome expectations of smoking: implications for prevention. Prev Med 29:460-465. David V., Besson M., Changeux J. P., Granon S., Cazala P. (2006) Reinforcing effects of nicotine microinjections into the ventral tegmental area of mice: Dependence on cholinergic nicotinic and dopaminergic D1 receptors. Neuropharmacology 50:10301040. de Graaf-Peters V. B., Hadders-Algra M. (2006) Ontogeny of the human central nervous system: what is happening when? Early Hum Dev 82:257-266. De Graaf C., Zandstra E. H. (1999) Sweetness intensity and pleasantness in children, adolescents, and adults. Physiol Behav 67:513-520. De Souza E. B., Kuhar M. J. (1984) Dopamine receptors in the anterior lobe of the human pituitary gland: autoradiographic localization. Brain Res 306:391-395. de Wit H., Stewart J. (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75:134-143. de Wit H., Stewart J. (1983) Drug reinstatement of heroin-reinforced responding in the rat. Psychopharmacology 79:29-31. Deakin J., Aitken M., Robbins T., Sahakian B. J. (2004) Risk taking during decisionmaking in normal volunteers changes with age. J Int Neuropsychol Soc 10:590-598. Delville Y., David J. T., Taravosh-Lahn K., Wommack J. C. (2003) Stress and the development of agonistic behavior in golden hamsters. Horm Behav 44:263-270. Deminiere J. M., Piazza P. V., Le Moal M., Simon H. (1989) Experimental approach to individual vulnerability to psychostimulant addiction. Neurosci Biobehav Rev 13:141-147. DeNoble V. J., Mele P. C. (2006) Intravenous nicotine self-administration in rats: effects of mecamylamine, hexamethonium and naloxone. Psychopharmacology (Berl) 184:266-272. Department of Health and Human Services U.S.A. (1994) Preventing tobacco use among young people: A report from the Surgeon General. Atlanta, GA: Centers for Disease Control, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. 224
Depoortere R. Y., Li D. H., Lane J. D., Emmett-Oglesby M. W. (1993) Parameters of selfadministration of cocaine in rats under a progressive-ratio schedule. Pharmacol Biochem Behav 45:539-548. Deroche-Gamonet V., Piat F., Le Moal M., Piazza P. V. (2002) Influence of cueconditioning on acquisition, maintenance and relapse of cocaine intravenous selfadministration. Eur J Neurosci 15:1363-1370. DeWit D. J., Offord D. R., Wong M. (1997) Patterns of onset and cessation of drug use over the early part of the life course. Health Educ Behav 24:746-758. Di Chiara G. (1999) Drug addiction as dopamine-dependent associative learning disorder. Eur J Pharmacol 375:13-30. Di Chiara G. (2000) Role of dopamine in the behavioural actions of nicotine related to addiction. Eur J Pharmacol 393:295-314. Di Chiara G., Imperato A. (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274-5278. Di Chiara G., Bassareo V., Fenu S., De Luca M. A., Spina L., Cadoni C., Acquas E., Carboni E., Valentini V., Lecca D. (2004) Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47:227-241. DiFranza J. R., Rigotti N. A., McNeill A. D., Ockene J. K., Savageau J. A., St Cyr D., Coleman M. (2000) Initial symptoms of nicotine dependence in adolescents. Tob Control 9:313-319. DiFranza J. R., Savageau J. A., Rigotti N. A., Fletcher K., Ockene J. K., McNeill A. D., Coleman M., Wood C. (2002) Development of symptoms of tobacco dependence in youths: 30 month follow up data from the DANDY study. Tob Control 11:228-235. DiFranza J. R., Savageau J. A., Fletcher K., Ockene J. K., Rigotti N. A., McNeill A. D., Coleman M., Wood C. (2004) Recollections and repercussions of the first inhaled cigarette. Addict Behav 29:261-272. Ding A. (2003) Youth are more sensitive to price changes in cigarettes than adults. Yale J Biol Med 76:115-124. Dinn W. M., Aycicegi A., Harris C. L. (2004) Cigarette smoking in a student sample: neurocognitive and clinical correlates. Addict Behav 29:107-126. Donny E. C., Bigelow G. E., Walsh S. L. (2006) Comparing the physiological and subjective effects of self-administered vs yoked cocaine in humans. Psychopharmacology (Berl) 186:544-552. Donny E. C., Caggiula A. R., Knopf S., Brown C. (1995) Nicotine self-administration in rats. Psychopharmacology (Berl) 122:390-394. Donny E. C., Caggiula A. R., Rose C., Jacobs K. S., Mielke M. M., Sved A. F. (2000) Differential effects of response-contingent and response-independent nicotine in rats. Eur J Pharmacol 402:231-240. Donny E. C., Lanza S. T., Balster R. L., Collins L. M., Caggiula A., Rowell P. P. (2004) Using growth models to relate acquisition of nicotine self-administration to break point and nicotinic receptor binding. Drug Alcohol Depend 75:23-35. Donny E. C., Caggiula A. R., Mielke M. M., Booth S., Gharib M. A., Hoffman A., Maldovan V., Shupenko C., McCallum S. E. (1999) Nicotine self-administration in rats on a progressive ratio schedule of reinforcement. Psychopharmacology (Berl) 147:135-142. 225
Doremus T. L., Brunell S. C., Rajendran P., Spear L. P. (2005) Factors influencing elevated ethanol consumption in adolescent relative to adult rats. Alcohol Clin Exp Res 29:1796-1808. Douglas L. A., Varlinskaya E. I., Spear L. P. (2003) Novel-object place conditioning in adolescent and adult male and female rats: effects of social isolation. Physiol Behav 80:317-325. Douglas L. A., Varlinskaya E. I., Spear L. P. (2004) Rewarding properties of social interactions in adolescent and adult male and female rats: impact of social versus isolate housing of subjects and partners. Dev Psychobiol 45:153-162. Dumont E. C., Mark G. P., Mader S., Williams J. T. (2005) Self-administration enhances excitatory synaptic transmission in the bed nucleus of the stria terminalis. Nat Neurosci 8:413-414. Dworkin S. I., Mirkis S., Smith J. E. (1995) Response-dependent versus responseindependent presentation of cocaine: differences in the lethal effects of the drug. Psychopharmacology (Berl) 117:262-266. Ehardt C.L., Bernstein I.S. (1987) Patterns of affiliaction among immature rhesus monkeys (macaca mulatta). American Journal of Primatology 13:255-269. Eissenberg T. (2004) Measuring the emergence of tobacco dependence: the contribution of negative reinforcement models. Addiction 99 Suppl 1:5-29. Eissenberg T., Balster R. L. (2000) Initial tobacco use episodes in children and adolescents: current knowledge, future directions. Drug Alcohol Depend 59 Suppl 1:S41-60. Elliott B. M., Faraday M. M., Phillips J. M., Grunberg N. E. (2004) Effects of nicotine on elevated plus maze and locomotor activity in male and female adolescent and adult rats. Pharmacol Biochem Behav 77:21-28. Elliott B. M., Faraday M. M., Phillips J. M., Grunberg N. E. (2005) Adolescent and adult female rats differ in sensitivity to nicotine's activity effects. Pharmacol Biochem Behav 80:567-575. Engberg G. (1989) Nicotine induced excitation of locus coeruleus neurons is mediated via release of excitatory amino acids. Life Sci 44:1535-1540. Epping-Jordan M. P., Watkins S. S., Koob G. F., Markou A. (1998) Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76-79. Epstein D. H., Preston K. L. (2003) The reinstatement model and relapse prevention: a clinical perspective. Psychopharmacology (Berl) 168:31-41. Epstein D. H., Preston K. L., Stewart J., Shaham Y. (2006) Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology (Berl) 189:1-16. Erb S., Shaham Y., Stewart J. (1996) Stress reinstates cocaine-seeking behavior after prolonged extinction and a drug-free period. Psychopharmacology (Berl) 128:408412. Etscorn F., Moore G. A., Scott E. P., Hagen L. S., Caton T. M., Sanders D. L., Divine K. K. (1987) Conditioned saccharin aversions in rats as a result of cutaneous nicotine or intraperitoneal nicotine administered in divided doses. Pharmacol Biochem Behav 28:495-502. Etter J. F., Stapleton J. A. (2006) Nicotine replacement therapy for long-term smoking cessation: a meta-analysis. Tob Control 15:280-285.
226
Evans A. H., Lees A. J. (2004) Dopamine dysregulation syndrome in Parkinson's disease. Curr Opin Neurol 17:393-398. Everett S. A., Husten C. G., Kann L., Warren C. W., Sharp D., Crossett L. (1999) Smoking initiation and smoking patterns among US college students. J Am Coll Health 48:55-60. Fattore L., Cossu G., Martellotta M. C., Fratta W. (2002) Baclofen antagonizes intravenous self-administration of nicotine in mice and rats. Alcohol Alcohol 37:495-498. Fernandez E., Schiaffino A., La Vecchia C., Borras J. M., Nebot M., Salto E., Tresserras R., Rajmil L., Villalbi J. R., Segura A. (1999) Age at starting smoking and number of cigarettes smoked in Catalonia, Spain. Prev Med 28:361-366. Ferris C. F. (2003) Using an animal model to assess the long-term behavioral and biological consequences of adolescent abuse and exposure to alcohol. Ann N Y Acad Sci 1008:69-78. Fibiger H. C., Phillips A. G. (1988) Mesocorticolimbic dopamine systems and reward. Ann N Y Acad Sci 537:206-215. Fidler T. L., Bakner L., Cunningham C. L. (2004) Conditioned place aversion induced by intragastric administration of ethanol in rats. Pharmacol Biochem Behav 77:731743. File S. E., Kenny P. J., Ouagazzal A. M. (1998) Bimodal modulation by nicotine of anxiety in the social interaction test: role of the dorsal hippocampus. Behav Neurosci 112:1423-1429. File S. E., Cheeta S., Kenny P. J. (2000) Neurobiological mechanisms by which nicotine mediates different types of anxiety. Eur J Pharmacol 393:231-236. Flay B. R., Hu F. B., Richardson J. (1998) Psychosocial predictors of different stages of cigarette smoking among high school students. Prev Med 27:A9-18. Flay B. R., Hu F. B., Siddiqui O., Day L. E., Hedeker D., Petraitis J., Richardson J., Sussman S. (1994) Differential influence of parental smoking and friends' smoking on adolescent initiation and escalation of smoking. J Health Soc Behav 35:248-265. Fletcher P. J., Rizos Z., Sinyard J., Tampakeras M., Higgins G. A. (2007) The 5-HT(2C) Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues. Neuropsychopharmacology, in press. Forget B., Hamon M., Thiebot M. H. (2005) Cannabinoid CB1 receptors are involved in motivational effects of nicotine in rats. Psychopharmacology (Berl) 181:722-734. Epub 2005 Sep 2029. Frantz K. J., O'Dell L. E., Parsons L. H. (2007) Behavioral and neurochemical responses to cocaine in periadolescent and adult rats. Neuropsychopharmacology 32:625-637. Freedman L. J., Cassell M. D. (1994) Distribution of dopaminergic fibers in the central division of the extended amygdala of the rat. Brain Res 633:243-252. Fudala P. J., Iwamoto E. T. (1986) Further studies on nicotine-induced conditioned place preference in the rat. Pharmacol Biochem Behav 25:1041-1049. Fudala P. J., Teoh K. W., Iwamoto E. T. (1985) Pharmacologic characterization of nicotine-induced conditioned place preference. Pharmacol Biochem Behav 22:237241.
227
Fung Y. K., Schmid M. J., Anderson T. M., Lau Y. S. (1996) Effects of nicotine withdrawal on central dopaminergic systems. Pharmacol Biochem Behav 53:635640. Funk D., Vohra S., Le A. D. (2004) Influence of stressors on the rewarding effects of alcohol in Wistar rats: studies with alcohol deprivation and place conditioning. Psychopharmacology (Berl) 176:82-87. Funk D., Li Z., Shaham Y., Le A. D. (2003) Effect of blockade of corticotropin-releasing factor receptors in the median raphe nucleus on stress-induced c-fos mRNA in the rat brain. Neuroscience 122:1-4. Garcia R., Jaffard R. (1992) The hippocampo-septal projection in mice: long-term potentiation in the lateral septum. Neuroreport 3:193-196. Gardner E. L. (2000) What we have learned about addiction from animal models of drug self-administration. Am J Addict 9:285-313. GeneDetect (2001) In-situ hybridization using GeneDetect oligonucleotide probes: 35Slabeled probe, frozen tissue sections. Detection by emulsion or film autoradiography.: www.genedetect.com/protocols.htm. Gervais A., O'Loughlin J., Meshefedjian G., Bancej C., Tremblay M. (2006) Milestones in the natural course of onset of cigarette use among adolescents. CMAJ 175:255-261. Ghosheh O., Hawes E. M. (2002) Microsomal N-glucuronidation of nicotine and cotinine: human hepatic interindividual, human intertissue, and interspecies hepatic variation. Drug Metab Dispos 30:1478-1483. Ghosheh O. A., Dwoskin L. P., Miller D. K., Crooks P. A. (2001) Accumulation of nicotine and its metabolites in rat brain after intermittent or continuous peripheral administration of [2'-(14)C]nicotine. Drug Metab Dispos 29:645-651. Giedd J. N. (2004) Structural magnetic resonance imaging of the adolescent brain. Ann N Y Acad Sci 1021:77-85. Giedd J. N., Blumenthal J., Jeffries N. O., Castellanos F. X., Liu H., Zijdenbos A., Paus T., Evans A. C., Rapoport J. L. (1999) Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci 2:861-863. Gilbert D. G., Gilbert B. O. (1995) Personality, psychopathology, and nicotine response as mediators of the genetics of smoking. Behav Genet 25:133-147. Goeders N. E. (2002) The HPA axis and cocaine reinforcement. Psychoneuroendocrinology 27:13-33. Goeders N. E., Guerin G. F. (1996) Role of corticosterone in intravenous cocaine selfadministration in rats. Neuroendocrinology 64:337-348. Gogtay N., Giedd J. N., Lusk L., Hayashi K. M., Greenstein D., Vaituzis A. C., Nugent T. F., 3rd, Herman D. H., Clasen L. S., Toga A. W., Rapoport J. L., Thompson P. M. (2004) Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci U S A 101:8174-8179. Goldberg S. R., Gardner M. L. (1981) Second-order schedules: extended sequences of behavior controlled by brief environmental stimuli associated with drug selfadministration. NIDA Res Monogr 37:241-270. Gotti C., Clementi F. (2004) Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 74:363-396. Gould E., Woolf N. J., Butcher L. L. (1991) Postnatal development of cholinergic neurons in the rat: I. Forebrain. Brain Res Bull 27:767-789. 228
Grabus S. D., Martin B. R., Batman A. M., Tyndale R. F., Sellers E., Damaj M. I. (2005) Nicotine physical dependence and tolerance in the mouse following chronic oral administration. Psychopharmacology (Berl) 178:183-192. Grant B. F. (1998) Age at smoking onset and its association with alcohol consumption and DSM-IV alcohol abuse and dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abuse 10:59-73. Grant B. F., Dawson D. A. (1998) Age of onset of drug use and its association with DSMIV drug abuse and dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abuse 10:163-173. Grant B.F., Dawson D.A. (1997) Age at onset of alcohol use and its association with DSMIV alcohol abuse and dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abuse 9:103-110. Green T. A., Phillips S. B., Crooks P. A., Dwoskin L. P., Bardo M. T. (2000) Nornicotine pretreatment decreases intravenous nicotine self-administration in rats. Psychopharmacology (Berl) 152:289-294. Griffiths R. R., Balster R. L. (1979) Opioids: similarity between evaluations of subjective effects and animal self-administration results. Clin Pharmacol Ther 25:611-617. Grigson P. S. (1997) Conditioned taste aversions and drugs of abuse: a reinterpretation. Behav Neurosci 111:129-136. Grimm J. W., Hope B. T., Wise R. A., Shaham Y. (2001) Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412:141-142. Guilarte T. R., McGlothan J. L. (1998) Hippocampal NMDA receptor mRNA undergoes subunit specific changes during developmental lead exposure. Brain Res 790:98107. Hahn B., Shoaib M., Stolerman I. P. (2003) Involvement of the prefrontal cortex but not the dorsal hippocampus in the attention-enhancing effects of nicotine in rats. Psychopharmacology (Berl) 168:271-279. Hamada Y., Hayakawa S., Suzuki J., Ohkura S. (1999) Adolescent growth and development in Japanese macaques (Macaca fuscata): Punctuated adolescent growth spurt by season. Primates 40:439-452. Hamilton K.R., Shager S.T., Perry M.E., Marwein M., Grunberg N. E. (2006) Nicotine withdrawal in adult female rats. In: Society for Research on Nicotine and Tobacco. Orlando, FL. Hammond D. K., Bjercke R. J., Langone J. J., Strobel H. W. (1991) Metabolism of nicotine by rat liver cytochromes P-450. Assessment utilizing monoclonal antibodies to nicotine and cotinine. Drug Metab Dispos 19:804-808. Han C., McGue M. K., Iacono W. G. (1999) Lifetime tobacco, alcohol and other substance use in adolescent Minnesota twins: univariate and multivariate behavioral genetic analyses. Addiction 94:981-993. Hanna E. Z., Grant B. F. (1999) Parallels to early onset alcohol use in the relationship of early onset smoking with drug use and DSM-IV drug and depressive disorders: findings from the National Longitudinal Epidemiologic Survey. Alcohol Clin Exp Res 23:513-522. Hanna E. Z., Yi H. Y., Dufour M. C., Whitmore C. C. (2001) The relationship of earlyonset regular smoking to alcohol use, depression, illicit drug use, and other risky
229
behaviors during early adolescence: results from the youth supplement to the third national health and nutrition examination survey. J Subst Abuse 13:265-282. Happaney K., Zelazo P. D., Stuss D. T. (2004) Development of orbitofrontal function: current themes and future directions. Brain Cogn 55:1-10. Harvey D. M., Yasar S., Heishman S. J., Panlilio L. V., Henningfield J. E., Goldberg S. R. (2004) Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Psychopharmacology (Berl) 175:134-142. Hasue R. H., Shammah-Lagnado S. J. (2002) Origin of the dopaminergic innervation of the central extended amygdala and accumbens shell: a combined retrograde tracing and immunohistochemical study in the rat. J Comp Neurol 454:15-33. Health Canada (2003) Smoking in Canada: An overview. http://www.hc-sc.gc.ca/hlvs/alt_formats/hecs-sesc/pdf/tobac-tabac/research-recherche/stat/ctums-esutc/fsif/2003/2003-smok-fum_e.pdf. Health Canada (2006a) Canadian Tobacco Use Monitoring Survey: Results from the first half of 2006 (February-June). http://www.hc-sc.gc.ca/hl-vs/tobac-tabac/researchrecherche/stat/ctums-esutc/2006/wave-phase-1_summary-sommaire_e.html. Health Canada (2006b) Youth Smoking Survey, 2004-2005. In: http://wwwhc-scgcca/hlvs/alt_formats/hecs-sesc/pdf/tobac-tabac/research-recherche/stat/surveysondage/2004-2005/yss-2004-2005_epdf. Heijtz R. D., Ogren S. O., Fuxe K. (2000) Ontogeny of the motor inhibitory role of dopamine D(3) receptor subtype in rats. Eur J Pharmacol 392:35-39. Helton D. R., Modlin D. L., Tizzano J. P., Rasmussen K. (1993) Nicotine withdrawal: a behavioral assessment using schedule controlled responding, locomotor activity, and sensorimotor reactivity. Psychopharmacology 113:205-210. Henningfield J. E., Goldberg S. R. (1983) Nicotine as a reinforcer in human subjects and laboratory animals. Pharmacol Biochem Behav 19:989-992. Henningfield J. E., Keenan R. M. (1993) Nicotine delivery kinetics and abuse liability. J Consult Clin Psychol 61:743-750. Henningfield J. E., Clayton R., Pollin W. (1990) Involvement of tobacco in alcoholism and illicit drug use. Br J Addict 85:279-291. Herning R. I., Jones R. T., Benowitz N. L., Mines A. H. (1983) How a cigarette is smoked determines blood nicotine levels. Clin Pharmacol Ther 33:84-90. Higgins G. A., Sellers E. M. (1994) Antagonist-precipitated opioid withdrawal in rats: evidence for dissociations between physical and motivational signs. Pharmacol Biochem Behav 48:1-8. Higgins G. A., Nguyen P., Sellers E. M. (1992) The NMDA antagonist dizocilpine (MK801) attenuates motivational as well as somatic aspects of naloxone precipitated opioid withdrawal. Life Sci 50:PL167-172. Hildebrand B. E., Panagis G., Svensson T. H., Nomikos G. G. (1999) Behavioral and biochemical manifestations of mecamylamine-precipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area. Neuropsychopharmacology 21:560-574. Hildebrand B. E., Nomikos G. G., Bondjers C., Nisell M., Svensson T. H. (1997) Behavioral manifestations of the nicotine abstinence syndrome in the rat: peripheral versus central mechanisms. Psychopharmacology (Berl) 129:348-356.
230
Hill K. G., Hawkins J. D., Catalano R. F., Abbott R. D., Guo J. (2005) Family influences on the risk of daily smoking initiation. J Adolesc Health 37:202-210. Hiranita T., Anggadiredja K., Fujisaki C., Watanabe S., Yamamoto T. (2004) Nicotine attenuates relapse to methamphetamine-seeking behavior (craving) in rats. Ann N Y Acad Sci 1025:504-507. Hoffman B. R., Sussman S., Unger J. B., Valente T. W. (2006) Peer influences on adolescent cigarette smoking: a theoretical review of the literature. Subst Use Misuse 41:103-155. Homberg J. R., van den Akker M., Raaso H. S., Wardeh G., Binnekade R., Schoffelmeer A. N., de Vries T. J. (2002) Enhanced motivation to self-administer cocaine is predicted by self-grooming behaviour and relates to dopamine release in the rat medial prefrontal cortex and amygdala. Eur J Neurosci 15:1542-1550. Hopfer C. J., Crowley T. J., Hewitt J. K. (2003) Review of twin and adoption studies of adolescent substance use. J Am Acad Child Adolesc Psychiatry 42:710-719. Huizinga M., van der Molen M. W. (2007) Age-group differences in set-switching and setmaintenance on the Wisconsin Card Sorting Task. Dev Neuropsychol 31:193-215. Huizinga M., Dolan C. V., van der Molen M. W. (2006) Age-related change in executive function: developmental trends and a latent variable analysis. Neuropsychologia 44:2017-2036. Hukkanen J., Jacob P., 3rd, Benowitz N. L. (2005) Metabolism and disposition kinetics of nicotine. Pharmacol Rev 57:79-115. Hunt T., Amit Z. (1987) Conditioned taste aversion induced by self-administered drugs: paradox revisited. Neurosci Biobehav Rev 11:107-130. Hunt W. A., Barnett L. W., Branch L. G. (1971) Relapse rates in addiction programs. J Clin Psychol 27:455-456. Huttenlocher P. R. (1979) Synaptic density in human frontal cortex - developmental changes and effects of aging. Brain Res 163:195-205. Huttenlocher P. R., Dabholkar A. S. (1997) Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 387:167-178. Ikemoto S., Qin M., Liu Z. H. (2006) Primary reinforcing effects of nicotine are triggered from multiple regions both inside and outside the ventral tegmental area. J Neurosci 26:723-730. Ilback N. G., Stalhandske T. (2003) Nicotine accumulation in the mouse brain is agedependent and is quantitatively different in various segments. Toxicol Lett 143:175184. Infurna R. N., Spear L. P. (1979) Developmental changes in amphetamine-induced taste aversions. Pharmacol Biochem Behav 11:31-35. Insel T. R., Miller L. P., Gelhard R. E. (1990) The ontogeny of excitatory amino acid receptors in rat forebrain--I. N-methyl-D-aspartate and quisqualate receptors. Neuroscience 35:31-43. Irvine E. E., Bagnalasta M., Marcon C., Motta C., Tessari M., File S. E., Chiamulera C. (2001) Nicotine self-administration and withdrawal: modulation of anxiety in the social interaction test in rats. Psychopharmacology (Berl) 153:315-320. Ise Y., Narita M., Nagase H., Suzuki T. (2000) Modulation of opioidergic system on mecamylamine-precipitated nicotine-withdrawal aversion in rats. Psychopharmacology (Berl) 151:49-54. 231
Iwamoto E. T., Williamson E. C. (1984) Nicotine-induced taste aversion: characterization and preexposure effects in rats. Pharmacol Biochem Behav 21:527-532. Jacobs E. H., Smit A. B., de Vries T. J., Schoffelmeer A. N. (2003) Neuroadaptive effects of active versus passive drug administration in addiction research. Trends Pharmacol Sci 24:566-573. Jacobsen L. K., Mencl W. E., Constable R. T., Westerveld M., Pugh K. R. (2007) Impact of smoking abstinence on working memory neurocircuitry in adolescent daily tobacco smokers. Psychopharmacology 16:16. Jacobsen L. K., Krystal J. H., Mencl W. E., Westerveld M., Frost S. J., Pugh K. R. (2005) Effects of smoking and smoking abstinence on cognition in adolescent tobacco smokers. Biol Psychiatry 57:56-66. Jaffe J.H. (1975) Drug addiction and drug abuse. In: The pharmacological basis of therapeutics (Goodman LS, Gilman A, eds), pp 284-324. New York: MacMillan. Jessor R., Jessor S.L. (1977) Problem behavior and psychosocial development: a longitudinal study of youth. New York: Academic Press. Johnson D. (2001) Age of illicit drug initiation. Trends and Issues in Crime and Criminal Justice 201:1-6. Johnston L.D., O'Malley P.M., Bachman J.G. (1998) National survey results on drug use from the Monitoring the Future study, 1975-1997. Volume I: Secondary school students. (NIH Publication No. 98-4345). Rockville, MD: National Institute on Drug Abuse, 433 pp. Johnston L.D., O’Malley P.M., Bachman J.G. (2001) Monitoring the Future national survey results on drug use, 1975-2000. Volume I: Secondary school students. (NIH Publication No. 01-4924). Bethesda, MD: National Insitute on Drug Abuse, 519 pp. Johnston L.D., O’Malley P.M., Bachman J.G., Schulenberg J.E. (2006) Monitoring the Future national survey results on drug use, 1975-2005: Volume I, Secondary school students. (NIH Publication No. 06-5883). Bethesda, MD: National Institute on Drug Abuse, 715 pp. Kabbaj M., Isgor C., Watson S. J., Akil H. (2002) Stress during adolescence alters behavioral sensitization to amphetamine. Neuroscience 113:395-400. Kalsbeek A., Voorn P., Buijs R. M., Pool C. W., Uylings H. B. (1988) Development of the dopaminergic innervation in the prefrontal cortex of the rat. J Comp Neurol 269:5872. Kandel D., Faust R. (1975) Sequence and stages in patterns of adolescent drug use. Arch Gen Psychiatry 32:923-932. Kandel D., Yamaguchi K. (1993) From beer to crack: developmental patterns of drug involvement. Am J Public Health 83:851-855. Kandel D. B., Chen K. (2000) Extent of smoking and nicotine dependence in the United States: 1991-1993. Nicotine Tob Res 2:263-274. Kandel D.B., Yamaguchi K., Chen K. (1992) Stages of progression in drug involvement from adolescence to adulthood: further evidence for the gateway theory. J Stud Alcohol 53:447-457. Kantak K. M., Goodrich C. M., Uribe V. (2007) Influence of sex, estrous cycle, and drugonset age on cocaine self-administration in rats (Rattus norvegicus). Exp Clin Psychopharmacol 15:37-47.
232
Karp I., O'Loughlin J., Hanley J., Tyndale R. F., Paradis G. (2006) Risk factors for tobacco dependence in adolescent smokers. Tob Control 15:199-204. Kashkin V. A., De Witte P. (2005) Nicotine increases microdialysate brain amino acid concentrations and induces conditioned place preference. Eur Neuropsychopharmacol 15:625-632. Kassel J. D., Stroud L. R., Paronis C. A. (2003) Smoking, stress, and negative affect: correlation, causation, and context across stages of smoking. Psychol Bull 129:270304. Kassel J. D., Evatt D. P., Greenstein J. E., Wardle M. C., Yates M. C., Veilleux J. C. (2007a) The acute effects of nicotine on positive and negative affect in adolescent smokers. J Abnorm Psychol 116:543-553. Kassel J. D., Greenstein J. E., Evatt D. P., Wardle M. C., Yates M. C., Veilleux J. C., Eissenberg T. (2007b) Smoking topography in response to denicotinized and highyield nicotine cigarettes in adolescent smokers. J Adolesc Health 40:54-60. Kelley A. E., Schochet T., Landry C. F. (2004) Risk taking and novelty seeking in adolescence: introduction to part I. Ann N Y Acad Sci 1021:27-32. Kelley B. J., Yeager K. R., Pepper T. H., Beversdorf D. Q. (2005) Cognitive impairment in acute cocaine withdrawal. Cogn Behav Neurol 18:108-112. Kelley B. M., Middaugh L. D. (1999) Periadolescent nicotine exposure reduces cocaine reward in adult mice. J Addict Dis 18:27-39. Kellogg C. K., Awatramani G. B., Piekut D. T. (1998) Adolescent development alters stressor-induced Fos immunoreactivity in rat brain. Neuroscience 83:681-689. Kiba H., Jayaraman A. (1994) Nicotine induced c-fos expression in the striatum is mediated mostly by dopamine D1 receptor and is dependent on NMDA stimulation. Brain Res Mol Brain Res 23:1-13. Killen J. D., Ammerman S., Rojas N., Varady J., Haydel F., Robinson T. N. (2001) Do adolescent smokers experience withdrawal effects when deprived of nicotine? Exp Clin Psychopharmacol 9:176-182. Koch M. (1996) The septohippocampal system is involved in prepulse inhibition of the acoustic startle response in rats. Behav Neurosci 110:468-477. Kokkevi A., Richardson C., Florescu S., Kuzman M., Stergar E. (2007) Psychosocial correlates of substance use in adolescence: a cross-national study in six European countries. Drug Alcohol Depend 86:67-74. Konkle A. T., Bielajew C. (2004) Tracing the neuroanatomical profiles of reward pathways with markers of neuronal activation. Rev Neurosci 15:383-414. Koob G. F. (2000) Animal models of drug addiction. In: Psychopharmacology: the fourth generation of progress: American College of Neuropsychopharmacology. Koob G. F. (2003) Neuroadaptive mechanisms of addiction: studies on the extended amygdala. Eur Neuropsychopharmacol 13:442-452. Koob G. F., Caine S. B., Parsons L., Markou A., Weiss F. (1997) Opponent process model and psychostimulant addiction. Pharmacol Biochem Behav 57:513-521. Koopmans J. R., van Doornen L. J., Boomsma D. I. (1997) Association between alcohol use and smoking in adolescent and young adult twins: a bivariate genetic analysis. Alcohol Clin Exp Res 21:537-546.
233
Koopmans J. R., Slutske W. S., Heath A. C., Neale M. C., Boomsma D. I. (1999) The genetics of smoking initiation and quantity smoked in Dutch adolescent and young adult twins. Behav Genet 29:383-393. Korenbrot C. C., Huhtaniemi I. T., Weiner R. I. (1977) Preputial separation as an external sign of pubertal development in the male rat. Biol Reprod 17:298-303. Korkosz A., Scinska A., Taracha E., Plaznik A., Kukwa A., Kostowski W., Bienkowski P. (2006) Nicotine-induced conditioned taste aversion in the rat: effects of ethanol. Eur J Pharmacol 537:99-105. Kosowski A. R., Liljequist S. (2005) Behavioural sensitization to nicotine precedes the onset of nicotine-conditioned locomotor stimulation. Behav Brain Res 156:11-17. Kostovic I. (1990) Structural and histochemical reorganization of the human prefrontal cortex during perinatal and postnatal life. In: Progress in brain research, the prefrontal cortex: its structure, function and pathology (Uylings HBM, Van Eden, C.G., De Bruin JPC, Corner MS, Feenstra MGP, eds), pp 223-240. Amsterdam: Elsevier. Kota D., Martin B. R., Robinson S. E., Damaj M. I. (2007) Nicotine dependence and reward differ between adolescent and adult male mice. J Pharmacol Exp Ther 322:399-407. Kovacs K. J. (1998) c-Fos as a transcription factor: a stressful (re)view from a functional map. Neurochem Int 33:287-297. Ksir C., Hakan R. L., Kellar K. J. (1987) Chronic nicotine and locomotor activity: influences of exposure dose and test dose. Psychopharmacology (Berl) 92:25-29. Kumar R., Pratt J. A., Stolerman I. P. (1983) Characteristics of conditioned taste aversion produced by nicotine in rats. Br J Pharmacol 79:245-253. Kyerematen G. A., Owens G. F., Chattopadhyay B., deBethizy J. D., Vesell E. S. (1988) Sexual dimorphism of nicotine metabolism and distribution in the rat. Studies in vivo and in vitro. Drug Metab Dispos 16:823-828. Lambert N. M., Hartsough C. S. (1998) Prospective study of tobacco smoking and substance dependencies among samples of ADHD and non-ADHD participants. J Learn Disabil 31:533-544. Lanca A. J., Adamson K. L., Coen K. M., Chow B. L., Corrigall W. A. (2000a) The pedunculopontine tegmental nucleus and the role of cholinergic neurons in nicotine self-administration in the rat: a correlative neuroanatomical and behavioral study. Neuroscience 96:735-742. Lanca J. A., Sanelli T. R., Corrigall W. A. (2000b) Nicotine-induced fos expression in the pedunculopontine mesencephalic tegmentum in the rat. Neuropharmacology 39:2808-2817. Lanier L. P., Isaacson R. L. (1977) Early developmental changes in the locomotor response to amphetamine and their relation to hippocampal function. Brain Res 126:567-575. Larson R., Richards M. H. (1991) Daily companionship in late childhood and early adolescence: changing developmental contexts. Child Dev 62:284-300. Laviola G., Dell'Omo G., Alleva E., Bignami G. (1992) Ontogeny of cocaine hyperactivity and conditioned place preference in mice. Psychopharmacology 107:221-228. Laviola G., Adriani W., Terranova M. L., Gerra G. (1999) Psychobiological risk factors for vulnerability to psychostimulants in human adolescents and animal models. Neurosci Biobehav Rev 23:993-1010. 234
Laviola G., Adriani W., Morley-Fletcher S., Terranova M. L. (2002) Peculiar response of adolescent mice to acute and chronic stress and to amphetamine: evidence of sex differences. Behav Brain Res 130:117-125. Laviola G., Macri S., Morley-Fletcher S., Adriani W. (2003) Risk-taking behavior in adolescent mice: psychobiological determinants and early epigenetic influence. Neurosci Biobehav Rev 27:19-31. Laviolette S. R., van der Kooy D. (2003) Blockade of mesolimbic dopamine transmission dramatically increases sensitivity to the rewarding effects of nicotine in the ventral tegmental area. Mol Psychiatry 8:50-59, 59. Laviolette S. R., van der Kooy D. (2004) The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nat Rev Neurosci 5:55-65. Laviolette S. R., Alexson T. O., van der Kooy D. (2002) Lesions of the tegmental pedunculopontine nucleus block the rewarding effects and reveal the aversive effects of nicotine in the ventral tegmental area. J Neurosci 22:8653-8660. Le A., Shaham Y. (2002) Neurobiology of relapse to alcohol in rats. Pharmacol Ther 94:137-156. Le A. D., Wang A., Harding S., Juzytsch W., Shaham Y. (2003) Nicotine increases alcohol self-administration and reinstates alcohol seeking in rats. Psychopharmacology (Berl) 168:216-221. Le A. D., Harding S., Juzytsch W., Funk D., Shaham Y. (2005) Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol selfadministration in rats. Psychopharmacology (Berl) 179:366-373. Le A. D., Li Z., Funk D., Shram M., Li T. K., Shaham Y. (2006) Increased vulnerability to nicotine self-administration and relapse in alcohol-naive offspring of rats selectively bred for high alcohol intake. J Neurosci 26:1872-1879. Le Foll B., Goldberg S. R. (2005) Nicotine induces conditioned place preferences over a large range of doses in rats. Psychopharmacology (Berl) 178:481-492. Le Foll B., Goldberg S. R., Sokoloff P. (2005) The dopamine D3 receptor and drug dependence: effects on reward or beyond? Neuropharmacology 49:525-541. Le Foll B., Wertheim C., Goldberg S. R. (2007) High reinforcing efficacy of nicotine in non-human primates. PLoS ONE 2:e230. Lecca D., Cacciapaglia F., Valentini V., Acquas E., Di Chiara G. (2007) Differential neurochemical and behavioral adaptation to cocaine after response contingent and noncontingent exposure in the rat. Psychopharmacology (Berl) 191:653-667. Lecca D., Cacciapaglia F., Valentini V., Gronli J., Spiga S., Di Chiara G. (2006) Preferential increase of extracellular dopamine in the rat nucleus accumbens shell as compared to that in the core during acquisition and maintenance of intravenous nicotine self-administration. Psychopharmacology (Berl) 184:435-446. Lee W., Nicklaus K. J., Manning D. R., Wolfe B. B. (1990) Ontogeny of cortical muscarinic receptor subtypes and muscarinic receptor-mediated responses in rat. J Pharmacol Exp Ther 252:482-490. LeSage M. G., Burroughs D., Pentel P. R. (2006) Effects of nicotine withdrawal on performance under a progressive-ratio schedule of sucrose pellet delivery in rats. Pharmacol Biochem Behav 83:585-591.
235
Leslie F. M., Loughlin S. E., Wang R., Perez L., Lotfipour S., Belluzzia J. D. (2004) Adolescent development of forebrain stimulant responsiveness: insights from animal studies. Ann N Y Acad Sci 1021:148-159. Levin E. D., McClernon F. J., Rezvani A. H. (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl) 184:523-539. Levin E. D., Rezvani A. H., Montoya D., Rose J. E., Swartzwelder H. S. (2003) Adolescent-onset nicotine self-administration modeled in female rats. Psychopharmacology (Berl) 169:141-149. Levin E. D., Lawrence S. S., Petro A., Horton K., Rezvani A. H., Seidler F. J., Slotkin T. A. (2007) Adolescent vs. adult-onset nicotine self-administration in male rats: Duration of effect and differential nicotinic receptor correlates. Neurotoxicol Teratol 2:2. Levy D., Gray-Donald K., Leech J., Zvagulis I., Pless I. B. (1986) Sleep patterns and problems in adolescents. J Adolesc Health Care 7:386-389. Lewinsohn P. M., Rohde P., Brown R. A. (1999) Level of current and past adolescent cigarette smoking as predictors of future substance use disorders in young adulthood. Addiction 94:913-921. Lewinsohn P. M., Brown R. A., Seeley J. R., Ramsey S. E. (2000) Psychosocial correlates of cigarette smoking abstinence, experimentation, persistence and frequency during adolescence. Nicotine Tob Res 2:121-131. Lewis D. A. (1997) Development of the prefrontal cortex during adolescence: insights into vulnerable neural circuits in schizophrenia. Neuropsychopharmacology 16:385-398. Linseman M. A. (1977) Naloxone-precipitated withdrawal as a function of the morphinenaloxone interval. Psychopharmacology (Berl) 54:159-164. Little P. J., Kuhn C. M., Wilson W. A., Swartzwelder H. S. (1996) Differential effects of ethanol in adolescent and adult rats. Alcohol Clin Exp Res 20:1346-1351. Liu X., Caggiula A. R., Yee S. K., Nobuta H., Poland R. E., Pechnick R. N. (2006) Reinstatement of nicotine-seeking behavior by drug-associated stimuli after extinction in rats. Psychopharmacology (Berl) 184:417-425. Lopez M.F., Simpson D.D., White N.M., Randall C.L. (2003) Age- and sex-related differences in alcohol and nicotine effects in C57BL/6J mice. Addiction Biology 8:419-427. Lynskey M. T., Hall W. (2001) Attention deficit hyperactivity disorder and substance use disorders: Is there a causal link? Addiction 96:815-822. Lynskey M. T., Fergusson D. M., Horwood L. J. (1998) The origins of the correlations between tobacco, alcohol, and cannabis use during adolescence. J Child Psychol Psychiatry 39:995-1005. Macri S., Adriani W., Chiarotti F., Laviola G. (2002) Risk taking during exploration of a plus-maze is greater in adolescent than in juvenile or adult mice. Animal Behaviour 64:541-546. Madhok T. C., Beyer H. S., Sharp B. M. (1994) Protein kinase A regulates nicotinic cholinergic receptors and subunit messenger ribonucleic acids in PC 12 cells. Endocrinology 134:91-96. Maes H. H., Woodard C. E., Murrelle L., Meyer J. M., Silberg J. L., Hewitt J. K., Rutter M., Simonoff E., Pickles A., Carbonneau R., Neale M. C., Eaves L. J. (1999) 236
Tobacco, alcohol and drug use in eight- to sixteen-year-old twins: the Virginia Twin Study of Adolescent Behavioral Development. J Stud Alcohol 60:293-305. Maggs J.L., Almeida D.M., Galambos N.L. (1995) Risky business: the paradoxical meaning of problem behavior for young adolescents. Journal of Early Adolescence 15:344-362. Maldonado A. M., Kirstein C. L. (2005a) Handling alters cocaine-induced activity in adolescent but not adult male rats. Physiol Behav 84:321-326. Maldonado A. M., Kirstein C. L. (2005b) Cocaine-induced locomotor activity is increased by prior handling in adolescent but not adult female rats. Physiol Behav 86:568572. Malin D. H. (2001) Nicotine dependence: studies with a laboratory model. Pharmacol Biochem Behav 70:551-559. Malin D. H., Lake J. R., Newlin-Maultsby P., Roberts L. K., Lanier J. G., Carter V. A., Cunningham J. S., Wilson O. B. (1992) Rodent model of nicotine abstinence syndrome. Pharmacol Biochem Behav 43:779-784. Mantsch J. R., Katz E. S. (2007) Elevation of glucocorticoids is necessary but not sufficient for the escalation of cocaine self-administration by chronic electric footshock stress in rats. Neuropsychopharmacology 32:367-376. Markham J. A., Morris J. R., Juraska J. M. (2007) Neuron number decreases in the rat ventral, but not dorsal, medial prefrontal cortex between adolescence and adulthood. Neuroscience 144:961-968. Markou A., Koob G. F. (1991) Postcocaine anhedonia. An animal model of cocaine withdrawal. Neuropsychopharmacology 4:17-26. Markou A., Koob G. F. (1993) Intracranial self-stimulation thresholds as a measure of reward. In: Behavioural Neuroscience: A Practical Approach (Sahgal A, ed), pp 93115. New York: IRL Press. Markou A., Paterson N. E. (2001) The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat. Nicotine Tob Res 3:361-373. Marks M. J., Campbell S. M., Romm E., Collins A. C. (1991) Genotype influences the development of tolerance to nicotine in the mouse. J Pharmacol Exp Ther 259:392402. Marubio L. M., del Mar Arroyo-Jimenez M., Cordero-Erausquin M., Lena C., Le Novere N., de Kerchove d'Exaerde A., Huchet M., Damaj M. I., Changeux J. P. (1999) Reduced antinociception in mice lacking neuronal nicotinic receptor subunits. Nature 398:805-810. Mathieu-Kia A. M., Pages C., Besson M. J. (1998) Inducibility of c-Fos protein in visuomotor system and limbic structures after acute and repeated administration of nicotine in the rat. Synapse 29:343-354. Matta S. G., Foster C. A., Sharp B. M. (1993) Nicotine stimulates the expression of cFos protein in the parvocellular paraventricular nucleus and brainstem catecholaminergic regions. Endocrinology 132:2149-2156. Matta S. G., Fu Y., Valentine J. D., Sharp B. M. (1998) Response of the hypothalamopituitary-adrenal axis to nicotine. Psychoneuroendocrinology 23:103-113. Matta S. G., Balfour D. J., Benowitz N. L., Boyd R. T., Buccafusco J. J., Caggiula A. R., Craig C. R., Collins A. C., Damaj M. I., Donny E. C., Gardiner P. S., Grady S. R., 237
Heberlein U., Leonard S. S., Levin E. D., Lukas R. J., Markou A., Marks M. J., McCallum S. E., Parameswaran N., Perkins K. A., Picciotto M. R., Quik M., Rose J. E., Rothenfluh A., Schafer W. R., Stolerman I. P., Tyndale R. F., Wehner J. M., Zirger J. M. (2007) Guidelines on nicotine dose selection for in vivo research. Psychopharmacology (Berl) 190:269-319. Mayer L. A., Parker L. A. (1993) Rewarding and aversive properties of IP and SC cocaine: assessment by place and taste conditioning. Psychopharmacology (Berl) 112:189194. McBride W. J., Murphy J. M., Ikemoto S. (1999) Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies. Behav Brain Res 101:129-152. McGue M., Elkins I., Iacono W. G. (2000) Genetic and environmental influences on adolescent substance use and abuse. Am J Med Genet 96:671-677. McMorrow M. J., Foxx R. M. (1983) Nicotine's role in smoking: an analysis of nicotine regulation. Psychol Bull 93:302-327. Meaney M. J., Stewart J. (1981) Neonatal-androgens influence the social play of prepubescent rats. Horm Behav 15:197-213. Messina E. S., Tyndale R. F., Sellers E. M. (1997) A major role for CYP2A6 in nicotine Coxidation by human liver microsomes. J Pharmacol Exp Ther 282:1608-1614. Mifsud J. C., Hernandez L., Hoebel B. G. (1989) Nicotine infused into the nucleus accumbens increases synaptic dopamine as measured by in vivo microdialysis. Brain Res 478:365-367. Miksys S., Hoffmann E., Tyndale R. F. (2000) Regional and cellular induction of nicotinemetabolizing CYP2B1 in rat brain by chronic nicotine treatment. Biochem Pharmacol 59:1501-1511. Milner P. M. (1991) Brain-stimulation reward: a review. Can J Psychol 45:1-36. Mirza N. R., Stolerman I. P. (1998) Nicotine enhances sustained attention in the rat under specific task conditions. Psychopharmacology (Berl) 138:266-274. Mombereau C., Lhuillier L., Kaupmann K., Cryan J. F. (2007) GABAB receptor-positive modulation-induced blockade of the rewarding properties of nicotine is associated with a reduction in nucleus accumbens DeltaFosB accumulation. J Pharmacol Exp Ther 321:172-177. Monti P. M., Miranda R., Jr., Nixon K., Sher K. J., Swartzwelder H. S., Tapert S. F., White A., Crews F. T. (2005) Adolescence: booze, brains, and behavior. Alcohol Clin Exp Res 29:207-220. Mucha R. F., Iversen S. D. (1984) Reinforcing properties of morphine and naloxone revealed by conditioned place preferences: a procedural examination. Psychopharmacology (Berl) 82:241-247. Mucha R. F., Kalant H., Linseman M. A. (1979) Quantitative relationships among measures of morphine tolerance and physical dependence in the rat. Pharmacol Biochem Behav 10:397-405. Mucha R. F., van der Kooy D., O'Shaughnessy M., Bucenieks P. (1982) Drug reinforcement studied by the use of place conditioning in rat. Brain Res 243:91-105. Naeff B., Schlumpf M., Lichtensteiger W. (1992) Pre- and postnatal development of highaffinity [3H]nicotine binding sites in rat brain regions: an autoradiographic study. Brain Res Dev Brain Res 68:163-174. 238
Nance D. M. (1983) The developmental and neural determinants of the effects of estrogen on feeding behavior in the rat: a theoretical perspective. Neurosci Biobehav Rev 7:189-211. Niemi R. R., Thompson W. R. (1980) Pavlovian excitation, internal inhibition, and their interaction with free operant avoidance as a function of age in rats. Dev Psychobiol 13:61-76. Nisell M., Nomikos G. G., Svensson T. H. (1994a) Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area. Synapse 16:36-44. Nisell M., Nomikos G. G., Svensson T. H. (1994b) Infusion of nicotine in the ventral tegmental area or the nucleus accumbens of the rat differentially affects accumbal dopamine release. Pharmacol Toxicol 75:348-352. Nomikos G. G., Hildebrand B. E., Panagis G., Svensson T. H. (1999) Nicotine withdrawal in the rat: role of alpha7 nicotinic receptors in the ventral tegmental area. Neuroreport 10:697-702. Nomikos G. G., Schilstrom B., Hildebrand B. E., Panagis G., Grenhoff J., Svensson T. H. (2000) Role of alpha7 nicotinic receptors in nicotine dependence and implications for psychiatric illness. Behav Brain Res 113:97-103. Nurse S., Lacaille J. C. (1999) Late maturation of GABA(B) synaptic transmission in area CA1 of the rat hippocampus. Neuropharmacology 38:1733-1742. O'Dell L. E., Koob G. F. (2007) 'Nicotine deprivation effect' in rats with intermittent 23hour access to intravenous nicotine self-administration. Pharmacol Biochem Behav 86:346-353. O'Dell L. E., Torres O. V., Natividad L. A., Tejeda H. A. (2007a) Adolescent nicotine exposure produces less affective measures of withdrawal relative to adult nicotine exposure in male rats. Neurotoxicol Teratol 29:17-22. O'Dell L. E., Bruijnzeel A. W., Smith R. T., Parsons L. H., Merves M. L., Goldberger B. A., Richardson H. N., Koob G. F., Markou A. (2006) Diminished nicotine withdrawal in adolescent rats: implications for vulnerability to addiction. Psychopharmacology (Berl) 186:612-619. O'Dell L. E., Chen S. A., Smith R. T., Specio S. E., Balster R. L., Paterson N. E., Markou A., Zorrilla E. P., Koob G. F. (2007b) Extended access to nicotine selfadministration leads to dependence: Circadian measures, withdrawal measures, and extinction behavior in rats. J Pharmacol Exp Ther 320:180-193. O'Loughlin J., DiFranza J., Tyndale R. F., Meshefedjian G., McMillan-Davey E., Clarke P. B., Hanley J., Paradis G. (2003) Nicotine-dependence symptoms are associated with smoking frequency in adolescents. Am J Prev Med 25:219-225. O'Loughlin J., Paradis G., Kim W., DiFranza J., Meshefedjian G., McMillan-Davey E., Wong S., Hanley J., Tyndale R. F. (2004) Genetically decreased CYP2A6 and the risk of tobacco dependence: a prospective study of novice smokers. Tob Control 13:422-428. Okamoto M., Kita T., Okuda H., Tanaka T., Nakashima T. (1994) Effects of aging on acute toxicity of nicotine in rats. Pharmacol Toxicol 75:1-6. Olausson P., Jentsch J. D., Taylor J. R. (2004) Nicotine enhances responding with conditioned reinforcement. Psychopharmacology (Berl) 171:173-178.
239
Olds J., Milner P. (1954) Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J Comp Physiol Psychol 47:419-427. Oliff H. S., Gallardo K. A. (1999) The effect of nicotine on developing brain catecholamine systems. Front Biosci 4:D883-897. Olmstead M. C. (2006) Animal models of drug addiction: Where do we go from here? Q J Exp Psychol (Colchester) 59:625-653. Ouagazzal A. M., Kenny P. J., File S. E. (1999) Modulation of behaviour on trials 1 and 2 in the elevated plus-maze test of anxiety after systemic and hippocampal administration of nicotine. Psychopharmacology (Berl) 144:54-60. Pak A. C., Ashby C. R., Jr., Heidbreder C. A., Pilla M., Gilbert J., Xi Z. X., Gardner E. L. (2006) The selective dopamine D3 receptor antagonist SB-277011A reduces nicotine-enhanced brain reward and nicotine-paired environmental cue functions. Int J Neuropsychopharmacol 9:585-602. Palma E., Bertrand S., Binzoni T., Bertrand D. (1996) Neuronal nicotinic alpha 7 receptor expressed in Xenopus oocytes presents five putative binding sites for methyllycaconitine. J Physiol 491:151-161. Pang Y., Kiba H., Jayaraman A. (1993) Acute nicotine injections induce c-fos mostly in non-dopaminergic neurons of the midbrain of the rat. Brain Res Mol Brain Res 20:162-170. Panksepp J. (1981) The ontogeny of play in rats. Dev Psychobiol 14:327-332. Papp M., Gruca P., Willner P. (2002) Selective blockade of drug-induced place preference conditioning by ACPC, a functional NDMA-receptor antagonist. Neuropsychopharmacology 27:727-743. Paredes R. G., Alonso A. (1997) Sexual behavior regulated (paced) by the female induces conditioned place preference. Behav Neurosci 111:123-128. Parker L. A. (1995) Rewarding drugs produce taste avoidance, but not taste aversion. Neurosci Biobehav Rev 19:143-157. Paterson D., Nordberg A. (2000) Neuronal nicotinic receptors in the human brain. Prog Neurobiol 61:75-111. Paterson N. E., Markou A. (2004) Prolonged nicotine dependence associated with extended access to nicotine self-administration in rats. Psychopharmacology (Berl) 173:6472. Paterson N. E., Markou A. (2005) The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats. Psychopharmacology (Berl) 179:255-261. Pawlak C. R., Schwarting R. K. (2005) Repeated nicotine treatment in rats with high versus low rearing activity: analyses of behavioural sensitisation and place preference. Psychopharmacology (Berl) 178:440-450. Paxinos G., Watson C. (1998) The rat brain in stereotaxic coordinates, 4th Edition. San Diego: Academic Press. Perkins K. A., Epstein L. H., Grobe J., Fonte C. (1994) Tobacco abstinence, smoking cues, and the reinforcing value of smoking. Pharmacol Biochem Behav 47:107-112. Perry M.E., Shafer S.T., Hamilton K.R., Marwein M., Grunberg N. E. (2006) Nicotine withdrawal in adolescent female rats. In: Society for Research on Nicotine and Tobacco. Orlando, FL.
240
Peto R., Lopez A. D., Boreham J., Thun M. (2006) Mortality from smoking in developed countries. 2nd Edition. Philpot R. M., Badanich K. A., Kirstein C. L. (2003) Place conditioning: age-related changes in the rewarding and aversive effects of alcohol. Alcohol Clin Exp Res 27:593-599. Piazza P. V., Deminiere J. M., Le Moal M., Simon H. (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511-1513. Piazza P. V., Deroche-Gamonent V., Rouge-Pont F., Le Moal M. (2000) Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction. J Neurosci 20:4226-4232. Piazza P. V., Rouge-Pont F., Deminiere J. M., Kharoubi M., Le Moal M., Simon H. (1991) Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration. Brain Res 567:169-174. Picciotto M. R., Corrigall W. A. (2002) Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics. J Neurosci 22:3338-3341. Picciotto M. R., Zoli M., Rimondini R., Lena C., Marubio L. M., Pich E. M., Fuxe K., Changeux J. P. (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391:173-177. Pidoplichko V. I., DeBiasi M., Williams J. T., Dani J. A. (1997) Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390:401-404. Pidoplichko V. I., Noguchi J., Areola O. O., Liang Y., Peterson J., Zhang T., Dani J. A. (2004) Nicotinic cholinergic synaptic mechanisms in the ventral tegmental area contribute to nicotine addiction. Learn Mem 11:60-69. Pomerleau O. F., Rosecrans J. (1989) Neuroregulatory effects of nicotine. Psychoneuroendocrinology 14:407-423. Pomerleau O. F., Pomerleau C. S., Namenek R. J. (1998) Early experiences with tobacco among women smokers, ex-smokers, and never-smokers. Addiction 93:595-599. Pomerleau O. F., Collins A. C., Shiffman S., Pomerleau C. S. (1993) Why some people smoke and others do not: new perspectives. J Consult Clin Psychol 61:723-731. Pontieri F. E., Tanda G., Orzi F., Di Chiara G. (1996) Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382:255-257. Post G. B., Kemper H. C. (1993) Nutrient intake and biological maturation during adolescence. The Amsterdam growth and health longitudinal study. Eur J Clin Nutr 47:400-408. Potter A. S., Newhouse P. A. (2004) Effects of acute nicotine administration on behavioral inhibition in adolescents with attention-deficit/hyperactivity disorder. Psychopharmacology (Berl) 176:182-194. Poulos C. X., Le A. D., Parker J. L. (1995) Impulsivity predicts individual susceptibility to high levels of alcohol self-administration. Behav Pharmacol 6:810-814. Poulsen L. H., Osler M., Roberts C., Due P., Damsgaard M. T., Holstein B. E. (2002) Exposure to teachers smoking and adolescent smoking behaviour: analysis of cross sectional data from Denmark. Tob Control 11:246-251. Pratt J. A., Stolerman I. P. (1984) Pharmacologically specific pretreatment effects on apomorphine-mediated conditioned taste aversions in rats. Pharmacol Biochem Behav 20:507-511. 241
Prokhorov A. V., Hudmon K. S., Cinciripini P. M., Marani S. (2005) "Withdrawal symptoms" in adolescents: a comparison of former smokers and never-smokers. Nicotine Tob Res 7:909-913. Pulvirenti L., Berrier R., Kreifeldt M., Koob G. F. (1994) Modulation of locomotor activity by NMDA receptors in the nucleus accumbens core and shell regions of the rat. Brain Res 664:231-236. Pyapali G. K., Turner D. A., Wilson W. A., Swartzwelder H. S. (1999) Age and dosedependent effects of ethanol on the induction of hippocampal long-term potentiation. Alcohol 19:107-111. Rada P., Jensen K., Hoebel B. G. (2001) Effects of nicotine and mecamylamine-induced withdrawal on extracellular dopamine and acetylcholine in the rat nucleus accumbens. Psychopharmacology (Berl) 157:105-110. Ramsey N. F., Van Ree J. M. (1993) Emotional but not physical stress enhances intravenous cocaine self-administration in drug-naive rats. Brain Res 608:216-222. Rasmussen T., Swedberg M. D. (1998) Reinforcing effects of nicotinic compounds: intravenous self-administration in drug-naive mice. Pharmacol Biochem Behav 60:567-573. Reinstein D. K., Isaacson R. L. (1977) Clonidine sensitivity in the developing rat. Brain Res 135:378-382. Rezvani A. H., Levin E. D. (2004) Adolescent and adult rats respond differently to nicotine and alcohol: motor activity and body temperature. Int J Dev Neurosci 22:349-354. Richardson N. R., Roberts D. C. (1996) Progressive ratio schedules in drug selfadministration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1-11. Risner M. E., Goldberg S. R. (1983) A comparison of nicotine and cocaine selfadministration in the dog: fixed-ratio and progressive-ratio schedules of intravenous drug infusion. J Pharmacol Exp Ther 224:319-326. Robinson T. E., Berridge K. C. (1993) The neural basis of drug craving: an incentivesensitization theory of addiction. Brain Res Brain Res Rev 18:247-291. Rodd-Henricks Z. A., Bell R. L., Kuc K. A., Murphy J. M., McBride W. J., Lumeng L., Li T. K. (2002a) Effects of ethanol exposure on subsequent acquisition and extinction of ethanol self-administration and expression of alcohol-seeking behavior in adult alcohol-preferring (P) rats: II. Adult exposure. Alcohol Clin Exp Res 26:1642-1652. Rodd-Henricks Z. A., Bell R. L., Kuc K. A., Murphy J. M., McBride W. J., Lumeng L., Li T. K. (2002b) Effects of ethanol exposure on subsequent acquisition and extinction of ethanol self-administration and expression of alcohol-seeking behavior in adult alcohol-preferring (P) rats: I. Periadolescent exposure. Alcohol Clin Exp Res 26:1632-1641. Rojas N. L., Killen J. D., Haydel K. F., Robinson T. N. (1998) Nicotine dependence among adolescent smokers. Arch Pediatr Adolesc Med 152:151-156. Rolls E. T. (2004) The functions of the orbitofrontal cortex. Brain Cogn 55:11-29. Romeo R. D., McEwen B. S. (2006) Stress and the adolescent brain. Ann N Y Acad Sci 1094:202-214. Rose J. E., Corrigall W. A. (1997) Nicotine self-administration in animals and humans: similarities and differences. Psychopharmacology (Berl) 130:28-40.
242
Rose J. E., Behm F. M., Westman E. C., Coleman R. E. (1999a) Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction. Drug Alcohol Depend 56:99-107. Rose J.S., Chassin L., Presson C.C., Sherman S.J. (1999b) Peer influences on adolescent smoking. A prospective sibling analysis. Merrill Palmer Quarterly 45:62-84. Rose R.M., Bernstein I.S., Gordon T.P., Lindsley J.G. (1978) Changes in testosterone and behavior during adolescence in the male Rhesus monkey. Psychosomatic Medicine 40:60-70. Rosenberg D. R., Lewis D. A. (1994) Changes in the dopaminergic innervation of monkey prefrontal cortex during late postnatal development: a tyrosine hydroxylase immunohistochemical study. Biol Psychiatry 36:272-277. Ross J. T., Corrigall W. A., Heidbreder C. A., Lesage M. G. (2007) Effects of the selective dopamine D(3) receptor antagonist SB-277011A on the reinforcing effects of nicotine as measured by a progressive-ratio schedule in rats. Eur J Pharmacol 559:173-179. Roth M. E., Carroll M. E. (2004) Sex differences in the acquisition of IV methamphetamine self-administration and subsequent maintenance under a progressive ratio schedule in rats. Psychopharmacology (Berl) 172:443-449. Russell M. A., Jarvis M. J., Feyerabend C., Saloojee Y. (1986) Reduction of tar, nicotine and carbon monoxide intake in low tar smokers. J Epidemiol Community Health 40:80-85. Rusted J. M., Mackee A., Williams R., Willner P. (1998) Deprivation state but not nicotine content of the cigarette affects responding by smokers on a progressive ratio task. Psychopharmacology (Berl) 140:411-417. Rutter M., Graham P., Chadwick O. F., Yule W. (1976) Adolescent turmoil: fact or fiction? J Child Psychol Psychiatry 17:35-56. Salamone J. D., Cousins M. S., Snyder B. J. (1997) Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis. Neurosci Biobehav Rev 21:341-359. Salamone J. D., Correa M., Farrar A., Mingote S. M. (2007) Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits. Psychopharmacology (Berl) 191:461-482. Salas R., Pieri F., De Biasi M. (2004) Decreased signs of nicotine withdrawal in mice null for the beta4 nicotinic acetylcholine receptor subunit. J Neurosci 24:10035-10039. Salminen O., Lahtinen S., Ahtee L. (1996) Expression of Fos protein in various rat brain areas following acute nicotine and diazepam. Pharmacol Biochem Behav 54:241248. Salminen O., Seppa T., Gaddnas H., Ahtee L. (2000) Effect of acute nicotine on Fos protein expression in rat brain during chronic nicotine and its withdrawal. Pharmacol Biochem Behav 66:87-93. Samaha A. N., Yau W. Y., Yang P., Robinson T. E. (2005) Rapid delivery of nicotine promotes behavioral sensitization and alters its neurobiological impact. Biol Psychiatry 57:351-360. Samson H. H., Czachowski C. L. (2003) Behavioral measures of alcohol selfadministration and intake control: rodent models. Int Rev Neurobiol 54:107-143.
243
Sanchis-Segura C., Spanagel R. (2006) Behavioural assessment of drug reinforcement and addictive features in rodents: an overview. Addict Biol 11:2-38. Sastry B. V., Chance M. B., Singh G., Horn J. L., Janson V. E. (1995) Distribution and retention of nicotine and its metabolite, cotinine, in the rat as a function of time. Pharmacology 50:128-136. Schenk S., Partridge B. (1997) Sensitization and tolerance in psychostimulant selfadministration. Pharmacol Biochem Behav 57:543-550. Schenk S., Partridge B. (1999) Cocaine-seeking produced by experimenter-administered drug injections: dose-effect relationships in rats. Psychopharmacology (Berl) 147:285-290. Schenk S., Robinson B., Amit Z. (1988) Housing conditions fail to affect the intravenous self-administration of amphetamine. Pharmacol Biochem Behav 31:59-62. Schenk S., Lacelle G., Gorman K., Amit Z. (1987) Cocaine self-administration in rats influenced by environmental conditions: implications for the etiology of drug abuse. Neurosci Lett 81:227-231. Scheufele P. M., Faraday M. M., Grunberg N. E. (2000) Nicotine administration interacts with housing conditions to alter social and non-social behaviors in male and female Long-Evans rats. Nicotine Tob Res 2:169-178. Schochet T. L., Kelley A. E., Landry C. F. (2004) Differential behavioral effects of nicotine exposure in adolescent and adult rats. Psychopharmacology (Berl) 175:265-273. Schochet T. L., Kelley A. E., Landry C. F. (2005) Differential expression of arc mRNA and other plasticity-related genes induced by nicotine in adolescent rat forebrain. Neuroscience 135:285-297. Schoedel K. A., Hoffmann E. B., Rao Y., Sellers E. M., Tyndale R. F. (2004) Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics 14:615-626. Schramm-Sapyta N. L., Pratt A. R., Winder D. G. (2004) Effects of periadolescent versus adult cocaine exposure on cocaine conditioned place preference and motor sensitization in mice. Psychopharmacology (Berl) 173:41-48. Schulteis G., Markou A., Cole M., Koob G. F. (1995) Decreased brain reward produced by ethanol withdrawal. Proc Natl Acad Sci U S A 92:5880-5884. Seeman P., Bzowej N. H., Guan H. C., Bergeron C., Becker L. E., Reynolds G. P., Bird E. D., Riederer P., Jellinger K., Watanabe S., et al. (1987) Human brain dopamine receptors in children and aging adults. Synapse 1:399-404. Sellings L. H., McQuade L. E., Clarke P. B. (2006) Evidence for multiple sites within rat ventral striatum mediating cocaine-conditioned place preference and locomotor activation. J Pharmacol Exp Ther 317:1178-1187. Sellings L.H.L., McQuade L., Clarke P.B.S. (2005) Different nucleus accumbens subregions mediate the rewarding and aversive effects of nicotine. In: 2nd Annual Invitational Symposium for Research to Inform Tobacco Control. Toronto, Canada. Seppa T., Salminen O., Moed M., Ahtee L. (2001) Induction of Fos-immunostaining by nicotine and nicotinic receptor antagonists in rat brain. Neuropharmacology 41:486495. Seth P., Cheeta S., Tucci S., File S. E. (2002) Nicotinic--serotonergic interactions in brain and behaviour. Pharmacol Biochem Behav 71:795-805. 244
Shaham Y., Stewart J. (1996) Effects of opioid and dopamine receptor antagonists on relapse induced by stress and re-exposure to heroin in rats. Psychopharmacology (Berl) 125:385-391. Shaham Y., Adamson L. K., Grocki S., Corrigall W. A. (1997) Reinstatement and spontaneous recovery of nicotine seeking in rats. Psychopharmacology (Berl) 130:396-403. Shaham Y., Shalev U., Lu L., De Wit H., Stewart J. (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168:3-20. Shedler J., Block J. (1990) Adolescent drug use and psychological health. A longitudinal inquiry. Am Psychol 45:612-630. Sheehan T. P., Chambers R. A., Russell D. S. (2004) Regulation of affect by the lateral septum: implications for neuropsychiatry. Brain Res Brain Res Rev 46:71-117. Shepard J. D., Bossert J. M., Liu S. Y., Shaham Y. (2004) The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse. Biol Psychiatry 55:1082-1089. Shimada M., Murayama N., Yamazoe Y., Hashimoto H., Ishikawa H., Kato R. (1995) Ageand sex-related alterations of microsomal drug- and testosterone-oxidizing cytochrome P450 in Sprague-Dawley strain-derived dwarf rats. J Pharmacol Exp Ther 275:972-977. Shoaib M. (1996) Determinants of nicotine self-administration. Drug Development Research 38:212-221. Shoaib M., Stolerman I. P. (1995) Conditioned taste aversions in rats after intracerebral administration of nicotine. Behav Pharmacol 6:375-385. Shoaib M., Stolerman I. P. (1999) Plasma nicotine and cotinine levels following intravenous nicotine self-administration in rats. Psychopharmacology (Berl) 143:318-321. Shoaib M., Stolerman I. P., Kumar R. C. (1994) Nicotine-induced place preferences following prior nicotine exposure in rats. Psychopharmacology (Berl) 113:445-452. Shoaib M., Schindler C. W., Goldberg S. R. (1997) Nicotine self-administration in rats: strain and nicotine pre-exposure effects on acquisition. Psychopharmacology (Berl) 129:35-43. Shoaib M., Gommans J., Morley A., Stolerman I. P., Grailhe R., Changeux J. P. (2002) The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion. Neuropharmacology 42:530-539. Shram M. J., Funk D., Li Z., Le A. D. (2006) Periadolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine. Psychopharmacology (Berl) 186:201-208. Shram M. J., Funk D., Li Z., Le A. D. (2007a) Acute nicotine enhances c-fos mRNA expression differentially in reward-related substrates of adolescent and adult rat brain. Neurosci Lett 21:21. Shram M.J., Lê A.D. (in preparation) Nicotine, at a self-administered dose, induces a conditioned place preference in adolescent, but not adult rats. Shram M.J., Li Z., Lê A.D. (2007c) Age differences in the spontaneous acquisition of nicotine self-administration in male Wistar and Long Evans rats, Psychopharmacology, in press. 245
Shram M.J., Funk D., Li Z., Lê A.D. (2007b) Nicotine self-administration, extinction and reinstatement in adolescent and adult male rats: evidence against a biological vulnerability to nicotine addiction during adolescence. Neuropsychopharmacology in press. Shram M.J., Siu E. C., Li Z., Tyndale R. F., Lê A.D. (submitted) Adolescent and adult rats respond differently to the aversive effects of mecamylamine-precipitated nicotine withdrawal. Silagy C., Lancaster T., Stead L., Mant D., Fowler G. (2004) Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 3. Silveri M. M., Spear L. P. (1998) Decreased sensitivity to the hypnotic effects of ethanol early in ontogeny. Alcohol Clin Exp Res 22:670-676. Silveri M. M., Spear L. P. (2000) Ontogeny of ethanol elimination and ethanol-induced hypothermia. Alcohol 20:45-53. Simons-Morton B., Haynie D. L., Crump A. D., Eitel S. P., Saylor K. E. (2001) Peer and parent influences on smoking and drinking among early adolescents. Health Educ Behav 28:95-107. Singer S., Rossi S., Verzosa S., Hashim A., Lonow R., Cooper T., Sershen H., Lajtha A. (2004) Nicotine-induced changes in neurotransmitter levels in brain areas associated with cognitive function. Neurochem Res 29:1779-1792. Sisk C. L., Zehr J. L. (2005) Pubertal hormones organize the adolescent brain and behavior. Front Neuroendocrinol 26:163-174. Siu E. C., Wildenauer D. B., Tyndale R. F. (2006) Nicotine self-administration in mice is associated with rates of nicotine inactivation by CYP2A5. Psychopharmacology (Berl) 184:401-408. Sizemore G. M., Cannon D. G., Smith J. E., Dworkin S. I. (2003) The effects of acutely administered cocaine on responding maintained by a progressive-ratio schedule of food presentation. Behav Pharmacol 14:33-40. Sizonenko P. C. (1989) Physiology of puberty. J Endocrinol Invest 12(8:59-63. Skjei K. L., Markou A. (2003) Effects of repeated withdrawal episodes, nicotine dose, and duration of nicotine exposure on the severity and duration of nicotine withdrawal in rats. Psychopharmacology (Berl) 168:280-292. Sklar C. A., Kaplan S. L., Grumbach M. M. (1980) Evidence for dissociation between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis, isolated gonadotropin deficiency, and constitutionally delayed growth and adolescence. J Clin Endocrinol Metab 51:548-556. Slawecki C. J. (2005) Comparison of anxiety-like behavior in adolescent and adult Sprague-Dawley rats. Behav Neurosci 119:1477-1483. Slotkin T. A. (2002) Nicotine and the adolescent brain: insights from an animal model. Neurotoxicol Teratol 24:369-384. Slovic P. (2000) What does it mean to know a cumulative risk? Adolescent's perceptions of short-term and long-term consequences of smoking. Journal of Behavioral Decision Making 13:259-266. Smith A. M., Kelly R. B., Chen W. J. (2002) Chronic continuous nicotine exposure during periadolescence does not increase ethanol intake during adulthood in rats. Alcohol Clin Exp Res 26:976-979.
246
Smith L. K., Forgie M. L., Pellis S. M. (1997) The postpubertal change in the playful defense of male rats depends upon neonatal exposure to gonadal hormones. Physiol Behav 63:151-155. Smith R. F. (2003) Animal models of periadolescent substance abuse. Neurotoxicol Teratol 25:291-301. Sowell E. R., Thompson P. M., Tessner K. D., Toga A. W. (2001) Mapping continued brain growth and gray matter density reduction in dorsal frontal cortex: Inverse relationships during postadolescent brain maturation. J Neurosci 21:8819-8829. Sowell E. R., Thompson P. M., Holmes C. J., Jernigan T. L., Toga A. W. (1999) In vivo evidence for post-adolescent brain maturation in frontal and striatal regions. Nat Neurosci 2:859-861. Spear L. P. (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417-463. Spear L. P., Brick J. (1979) Cocaine-induced behavior in the developing rat. Behav Neural Biol 26:401-415. Spear L. P., Brake S. C. (1983) Periadolescence: age-dependent behavior and psychopharmacological responsivity in rats. Dev Psychobiol 16:83-109. Spear L. P., Shalaby I. A., Brick J. (1980) Chronic administration of haloperidol during development: behavioral and psychopharmacological effects. Psychopharmacology 70:47-58. Spear L. P., Horowitz G. P., Lipovsky J. (1982) Altered behavioral responsivity to morphine during the periadolescent period in rats. Behav Brain Res 4:279-288. Spina L., Fenu S., Longoni R., Rivas E., Di Chiara G. (2006) Nicotine-conditioned singletrial place preference: selective role of nucleus accumbens shell dopamine D1 receptors in acquisition. Psychopharmacology (Berl) 184:447-455. Stafford D., LeSage M. G., Glowa J. R. (1998) Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review. Psychopharmacology (Berl) 139:169-184. Stansfield K. H., Kirstein C. L. (2006) Effects of novelty on behavior in the adolescent and adult rat. Dev Psychobiol 48:10-15. Stansfield K. H., Philpot R. M., Kirstein C. L. (2004) An animal model of sensation seeking: the adolescent rat. Ann N Y Acad Sci 1021:453-458. Stanwood G. D., McElligot S., Lu L., McGonigle P. (1997) Ontogeny of dopamine D3 receptors in the nucleus accumbens of the rat. Neurosci Lett 223:13-16. Steinberg L., Morris A. S. (2001) Adolescent development. Annu Rev Psychol 52:83-110. Stewart J. (2000) Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking. J Psychiatry Neurosci 25:125-136. Stewart J., de Wit H., Eikelboom R. (1984) Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychol Rev 91:251268. Stinus L., Le Moal M., Koob G. F. (1990) Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal. Neuroscience 37:767-773. Stolerman I. (1992) Drugs of abuse: behavioural principles, methods and terms. Trends Pharmacol Sci 13:170-176.
247
Stolerman I. P. (1988) Characterization of central nicotinic receptors by studies on the nicotine cue and conditioned taste aversion in rats. Pharmacol Biochem Behav 30:235-242. Stolerman I. P. (1999) Inter-species consistency in the behavioural pharmacology of nicotine dependence. Behav Pharmacol 10:559-580. Stone E. A., Quartermain D. (1997) Greater behavioral effects of stress in immature as compared to mature male mice. Physiol Behav 63:143-145. Substance Abuse and Mental Health Services Administration (2003) Overview of findings from the 2003 National Survey on Drug Use and Health. pp 14-21: Department of Health and Human Services. Substance Abuse and Mental Health Services Administration (2005) Results from the 2005 national survey on drug use and health. Office of Applied Studies, NSDUH Series H-27, DHHS Publication No. SMA 05-4061. Suto N., Austin J. D., Vezina P. (2001) Locomotor response to novelty predicts a rat's propensity to self-administer nicotine. Psychopharmacology (Berl) 158:175-180. Suzuki T., Ise Y., Tsuda M., Maeda J., Misawa M. (1996) Mecamylamine-precipitated nicotine-withdrawal aversion in rats. Eur J Pharmacol 314:281-284. Swann J. W., Pierson M. G., Smith K. L., Lee C. L. (1999) Developmental neuroplasticity: roles in early life seizures and chronic epilepsy. Adv Neurol 79:203-216. Swanson L. W. (1982) The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull 9:321-353. Sziraki I., Sershen H., Hashim A., Lajtha A. (2002) Receptors in the ventral tegmental area mediating nicotine-induced dopamine release in the nucleus accumbens. Neurochem Res 27:253-261. Tarazi F. I., Tomasini E. C., Baldessarini R. J. (1998a) Postnatal development of dopamine D4-like receptors in rat forebrain regions: comparison with D2-like receptors. Brain Res Dev Brain Res 110:227-233. Tarazi F. I., Tomasini E. C., Baldessarini R. J. (1998b) Postnatal development of dopamine and serotonin transporters in rat caudate-putamen and nucleus accumbens septi. Neurosci Lett 254:21-24. Tarazi F. I., Tomasini E. C., Baldessarini R. J. (1999) Postnatal development of dopamine D1-like receptors in rat cortical and striatolimbic brain regions: An autoradiographic study. Dev Neurosci 21:43-49. Taylor P. (1993) Agents acting at the neuromuscular junction and autonomic ganglia. In: Goodman and Gilman's The pharmacological basis of therapeutics, 8th Edition (Goodman Gilman A, Rall TW, Nies AS, Taylor P, eds). New York: McGraw-Hill. Teicher M. H., Andersen S. L. (1999) Limbic serotonin turnover plunges during puberty. In: Society for Neuroscience. Miami, FL. Teicher M. H., Andersen S. L., Hostetter J. C., Jr. (1995) Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens. Brain Res Dev Brain Res 89:167-172. Teicher M. H., Krenzel E., Thompson A. P., Andersen S. L. (2003) Dopamine receptor pruning during the peripubertal period is not attenuated by NMDA receptor antagonism in rat. Neurosci Lett 339:169-171.
248
Teicher M. H., Barber N. I., Gelbard H. A., Gallitano A. L., Campbell A., Marsh E., Baldessarini R. J. (1993) Developmental differences in acute nigrostriatal and mesocorticolimbic system response to haloperidol. Neuropsychopharmacology 9:147-156. Terranova M. L., Laviola G. (2001) delta-Opioid modulation of social interactions in juvenile mice weaned at different ages. Physiol Behav 73:393-400. Tessari M., Pilla M., Andreoli M., Hutcheson D. M., Heidbreder C. A. (2004) Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking. Eur J Pharmacol 499:121-133. Thor D. H., Holloway W. R., Jr. (1984) Social play in juvenile rats: a decade of methodological and experimental research. Neurosci Biobehav Rev 8:455-464. Tirelli E., Laviola G., Adriani W. (2003a) Ontogenesis of behavioral sensitization and conditioned place preference induced by psychostimulants in laboratory rodents. Neurosci Biobehav Rev 27:163-178. Tirelli E., Tambour S., Michel A. (2003b) Sensitised locomotion does not predict conditioned locomotion in cocaine-treated mice: further evidence against the excitatory conditioning model of context-dependent sensitisation. Eur Neuropsychopharmacol 13:289-296. Torrella T. A., Badanich K. A., Philpot R. M., Kirstein C. L., Wecker L. (2004) Developmental differences in nicotine place conditioning. Ann N Y Acad Sci 1021:399-403. Trauth J. A., Seidler F. J., McCook E. C., Slotkin T. A. (1999) Adolescent nicotine exposure causes persistent upregulation of nicotinic cholinergic receptors in rat brain regions. Brain Res 851:9-19. Trauth J. A., Seidler F. J., Ali S. F., Slotkin T. A. (2001) Adolescent nicotine exposure produces immediate and long-term changes in CNS noradrenergic and dopaminergic function. Brain Res 892:269-280. Trimpop R.M., Kerr J.H., Kirkcaldy B. (1999) Comparing personality constructs of risktaking behavior. Personality and Individual Differences 26:237-254. Tung C. S., Grenhoff J., Svensson T. H. (1990) Nicotine counteracts midbrain dopamine cell dysfunction induced by prefrontal cortex inactivation. Acta Physiol Scand 138:427-428. Turner D. M. (1975) Influence of route of administration on metabolism of [14C]nicotine in four species. Xenobiotica 5:553-561. Turner D. M., Armitage A. K., Briant R. H., Dollery C. T. (1975) Metabolism of nicotine by the isolated perfused dog lung. Xenobiotica 5:539-551. Tyas S. L., Pederson L. L. (1998) Psychosocial factors related to adolescent smoking: a critical review of the literature. Tob Control 7:409-420. Tyndale R. F., Sellers E. M. (2002) Genetic variation in CYP2A6-mediated nicotine metabolism alters smoking behavior. Ther Drug Monit 24:163-171. Tzschentke T. M. (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56:613-672. U.S. Department of Health and Human Services (1989) Reducing the health consequences of smoking: 25 years of progress. pp 79-92. 249
Urbanski H. F., Ojeda S. R. (1987) Neuroendocrine mechanisms controlling the onset of female puberty. Reprod Toxicol 1:129-138. Vaidya J. G., Grippo A. J., Johnson A. K., Watson D. (2004) A comparative developmental study of impulsivity in rats and humans: the role of reward sensitivity. Ann N Y Acad Sci 1021:395-398. Vaisanen J., Ihalainen J., Tanila H., Castren E. (2004) Effects of NMDA-receptor antagonist treatment on c-fos expression in rat brain areas implicated in schizophrenia. Cell Mol Neurobiol 24:769-780. van den Bree M. B., Whitmer M. D., Pickworth W. B. (2004) Predictors of smoking development in a population-based sample of adolescents: a prospective study. J Adolesc Health 35:172-181. van der Kooy D., O'Shaughnessy M., Mucha R. F., Kalant H. (1983) Motivational properties of ethanol in naive rats as studied by place conditioning. Pharmacol Biochem Behav 19:441-445. Vann R. E., Balster R. L., Beardsley P. M. (2006) Dose, duration, and pattern of nicotine administration as determinants of behavioral dependence in rats. Psychopharmacology (Berl) 184:482-493. Vastola B. J., Douglas L. A., Varlinskaya E. I., Spear L. P. (2002) Nicotine-induced conditioned place preference in adolescent and adult rats. Physiol Behav 77:107114. Vega W. A., Gil A. G. (2005) Revisiting drug progression: long-range effects of early tobacco use. Addiction 100:1358-1369. Vetter C. S., Doremus-Fitzwater T. L., Spear L. P. (2007) Time course of elevated ethanol intake in adolescent relative to adult rats under continuous, voluntary-access conditions. Alcohol Clin Exp Res 31:1159-1168. Wall S. J., Yasuda R. P., Li M., Ciesla W., Wolfe B. B. (1992) The ontogeny of m1-m5 muscarinic receptor subtypes in rat forebrain. Brain Res Dev Brain Res 66:181-185. Walters C. L., Brown S., Changeux J. P., Martin B., Damaj M. I. (2006) The beta2 but not alpha7 subunit of the nicotinic acetylcholine receptor is required for nicotineconditioned place preference in mice. Psychopharmacology (Berl) 184:339-344. Watkins S. S., Epping-Jordan M. P., Koob G. F., Markou A. (1999) Blockade of nicotine self-administration with nicotinic antagonists in rats. Pharmacol Biochem Behav 62:743-751. Watkins S. S., Stinus L., Koob G. F., Markou A. (2000) Reward and somatic changes during precipitated nicotine withdrawal in rats: centrally and peripherally mediated effects. J Pharmacol Exp Ther 292:1053-1064. Wehrenberg W. B. (1986) The role of growth hormone-releasing factor and somatostatin on somatic growth in rats. Endocrinology 118:489-494. Weinshenker D., Schroeder J. P. (2007) There and back again: a tale of norepinephrine and drug addiction. Neuropsychopharmacology 32:1433-1451. Weiss F. (2005) Neurobiology of craving, conditioned reward and relapse. Curr Opin Pharmacol 5:9-19. Whalen C. K., Jamner L. D., Henker B., Delfino R. J. (2001) Smoking and moods in adolescents with depressive and aggressive dispositions: evidence from surveys and electronic diaries. Health Psychol 20:99-111.
250
White A. M., Swartzwelder H. S. (2004) Hippocampal function during adolescence: a unique target of ethanol effects. Ann N Y Acad Sci 1021:206-220. White A. M., Swartzwelder H. S. (2005) Age-related effects of alcohol on memory and memory-related brain function in adolescents and adults. Recent Dev Alcohol 17:161-176. White A. M., Truesdale M. C., Bae J. G., Ahmad S., Wilson W. A., Best P. J., Swartzwelder H. S. (2002) Differential effects of ethanol on motor coordination in adolescent and adult rats. Pharmacol Biochem Behav 73:673-677. White N. M. (1989) Reward or reinforcement: What's the difference. Neurosci Biobehav Rev 13:181-186. Wiley J. L., O'Connell M M., Tokarz M. E., Wright M. J., Jr. (2007) Pharmacological effects of acute and repeated administration of Delta(9)-tetrahydrocannabinol in adolescent and adult rats. J Pharmacol Exp Ther 320:1097-1105. Epub 2006 Dec 1015. Wilkins J. N., Carlson H. E., Van Vunakis H., Hill M. A., Gritz E., Jarvik M. E. (1982) Nicotine from cigarette smoking increases circulating levels of cortisol, growth hormone, and prolactin in male chronic smokers. Psychopharmacology 78:305-308. Willard J. C., Schoenborn C. A. (1995) Relationship between cigarette smoking and other unhealthy behaviors among our nation's youth: United States, 1992. Adv Data:1-11. Williams M., Robinson J. L. (1984) Binding of the nicotinic cholinergic antagonist, dihydro-beta-erythroidine, to rat brain tissue. J Neurosci 4:2906-2911. Willner P., Hardman S., Eaton G. (1995) Subjective and behavioural evaluation of cigarette cravings. Psychopharmacology (Berl) 118:171-177. Wills T. A., Resko J. A., Ainette M. G., Mendoza D. (2004) Smoking onset in adolescence: a person-centered analysis with time-varying predictors. Health Psychol 23:158167. Wills T.A., Mariani J., Filer M. (1996) The role of family and peer relationships in adolescent substance use. In: Handbook of social support and the family (Pierce GR, Sarason BR, Sarason IG, eds), pp 521-549. New York: Plenum Press. Wilmouth C. E., Spear L. P. (2004) Adolescent and adult rats' aversion to flavors previously paired with nicotine. Ann N Y Acad Sci 1021:462-464. Wilmouth C. E., Spear L. P. (2006) Withdrawal from chronic nicotine in adolescent and adult rats. Pharmacol Biochem Behav 85:648-657. Wilson J. M., Nobrega J. N., Corrigall W. A., Coen K. M., Shannak K., Kish S. J. (1994) Amygdala dopamine levels are markedly elevated after self- but not passiveadministration of cocaine. Brain Res 668:39-45. Wilson M., Daly M. (1985) Competitiveness, risk taking, and violence: the young male syndrome. Ethology and Sociobiology 6:59-73. Windle M., Windle R. C. (2001) Depressive symptoms and cigarette smoking among middle adolescents: prospective associations and intrapersonal and interpersonal influences. J Consult Clin Psychol 69:215-226. Wise R. A. (2004) Dopamine, learning and motivation. Nat Rev Neurosci 5:483-494. Wise R. A., Rompre P. P. (1989) Brain dopamine and reward. Annu Rev Psychol 40:191225. Wise R. A., Yokel R. A., DeWit H. (1976) Both positive reinforcement and conditioned aversion from amphetamine and from apomorphine in rats. Science 191:1273-1275. 251
Wise R. A., Murray A., Bozarth M. A. (1990) Bromocriptine self-administration and bromocriptine-reinstatement of cocaine-trained and heroin-trained lever pressing in rats. Psychopharmacology 100:355-360. Xi Z. X., Gilbert J. G., Pak A. C., Ashby C. R., Jr., Heidbreder C. A., Gardner E. L. (2005) Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats. Eur J Neurosci 21:3427-3438. Yokel R. A., Wise R. A. (1975) Increased lever pressing for amphetamine after pimozide in rats: implications for a dopamine theory of reward. Science 187:547-549. Yoshida M., Yokoo H., Tanaka T., Mizoguchi K., Emoto H., Ishii H., Tanaka M. (1993) Facilitatory modulation of mesolimbic dopamine neuronal activity by a mu-opioid agonist and nicotine as examined with in vivo microdialysis. Brain Res 624:277280. Young S.E., Rhee S.H., Stallings M.C., Corley R.P., Hewitt J.K. (2006) Genetic and environmental vulnerabilities underlying adolescent substance use and problem use: general or specific? Behavior Genetics 36:603-615. Yu J., Williford W. R. (1992) The age of alcohol onset and alcohol, cigarette, and marijuana use patterns: an analysis of drug use progression of young adults in New York State. Int J Addict 27:1313-1323. Yu Z. Y., Wang W., Fritschy J. M., Witte O. W., Redecker C. (2006) Changes in neocortical and hippocampal GABAA receptor subunit distribution during brain maturation and aging. Brain Res 1099:73-81. Zack M., Belsito L., Scher R., Eissenberg T., Corrigall W. A. (2001) Effects of abstinence and smoking on information processing in adolescent smokers. Psychopharmacology (Berl) 153:249-257. Zehr J. L., Todd B. J., Schulz K. M., McCarthy M. M., Sisk C. L. (2006) Dendritic pruning of the medial amygdala during pubertal development of the male Syrian hamster. J Neurobiol 66:578-590. Zhang M., Balmadrid C., Kelley A. E. (2003) Nucleus accumbens opioid, GABaergic, and dopaminergic modulation of palatable food motivation: contrasting effects revealed by a progressive ratio study in the rat. Behav Neurosci 117:202-211. Zhang X., Wahlstrom G., Nordberg A. (1990) Influence of development and aging on nicotinic receptor subtypes in rodent brain. Int J Dev Neurosci 8:715-721. Zhang X., Liu C., Miao H., Gong Z. H., Nordberg A. (1998) Postnatal changes of nicotinic acetylcholine receptor alpha 2, alpha 3, alpha 4, alpha 7 and beta 2 subunits genes expression in rat brain. Int J Dev Neurosci 16:507-518. Zuckerman M. (1994) Behavioral expressions and biosocial bases of sensation seeking. New York: Cambridge University Press.
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APPENDIX A: ADDITIONAL DATA Data not shown in Chapter 3: Adolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine
a Adolescents
b
Adults
Water consumed (ml)
10 8
Vehicle 0.2 mg/kg nicotine 0.4 mg/kg nicotine 0.8 mg/kg nicotine
6 4 2 0 1
2 3 Extinction trial
1
4
2 3 Extinction trial
4
Figure 21. Water consumption during extinction of a conditioned taste avoidance to a nicotinepaired saccharin solution in (a) adolescent and (b) adult male Wistar rats. Data points represent mean (±SEM) water consumed (ml) over four extinction trials. Animals received a free choice between saccharin and water during this phase. No nicotine was administered during the extinction phase. n = 6-8 per dose at each age.
253
Adolescent exposure to nicotine facilitates nicotine self-administration during adulthood (Manuscript in preparation)
Method Twenty adolescent (PD31) and 20 adult (PD88-91) male Long Evans rats were administered nicotine (0.4 mg/kg, s.c.) or vehicle daily for ten days. Four weeks later, rats were prepared with intravenous catheters. Following recovery from surgery (five weeks post-treatment), adolescent-pretreated (PD76) and adult-pretreated (PD133-136) rats selfadministered nicotine (0.03 mg/kg/infusion, i.v.) under a FR1 reinforcement schedule for four sessions, FR2 for four sessions and FR5 for five sessions, followed by PR testing for two sessions. The PR schedule was the same as in previous experiments (Depoortere et al., 1993; Donny et al., 1999; Shram et al., in press).
254
a
Infusions earned (1 h)
35
b
FR1*
FR2*
FR5*
35
30
30
25
25
20
20
15
15
10
10
5
5
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 adolescent vehicle-pretreated adolescent nicotine-pretreated
FR1
FR2
FR5
1 2 3 4 5 6 7 8 9 10 11 12 13 adult vehicle-pretreated adult nicotine-pretreated
Figure 22. Nicotine self-administration by rats pretreated with nicotine during adolescence or adulthood. Mean (±SEM) number of nicotine infusions earned in 1 h operant sessions under FR1, FR2 and FR5 reinforcement schedules in adult male rats pretreated with vehicle or nicotine (0.4 mg/kg, s.c., x 10 d) during (a) adolescence and (b) adulthood. n=10 per group. *p < .05 compared to vehicle-pretreated controls.
255
a
Active lever presses (1 h)
180 160
b
FR1*
FR2*
180
FR5*
160
140
140
120
120
100
100
80
80
60
60
40
40
20
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 adolescent vehicle-pretreated adolescent nicotine-pretreated
FR1
FR2
FR5
1 2 3 4 5 6 7 8 9 10 11 12 13 adult vehicle-pretreated adult nicotine-pretreated
Figure 23. Active lever responding for nicotine by rats pretreated with nicotine during adolescence or adulthood. Mean (±SEM) number of active lever presses in 1 h operant nicotine self-administration sessions under FR1, FR2 and FR5 reinforcement schedules in adult male rats pretreated with vehicle or nicotine (0.4 mg/kg, s.c., x 10 d) during (a) adolescence and (b) adulthood. n=10 per group. *p < .05 compared to vehicle-pretreated controls.
256
Active lever presses (2 h)
a
b
400
400
350
350
300
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250
250
200
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150
150
100
100
50
50
0
1
0
2
1
2
PR Session
PR Session
adolescent vehicle-pretreated
adult vehicle-pretreated
adolescent nicotine-pretreated
adult nicotine-pretreated
Figure 24. PR responding by rats pretreated with nicotine during adolescence or adulthood. Mean (±SEM) number of active lever presses in 2 h operant nicotine self-administration sessions under a progressive ratio reinforcement schedule in adult male rats pretreated with vehicle or nicotine (0.4 mg/kg, s.c., x 10 d) during a) adolescence and b) adulthood. n=10 per group. *p < .05 compared to vehicle-pretreated controls.
257
b
30
70
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70
25
60
25
60
50
20
40
15
30
10
20
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40
15
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5
10
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10
0
0
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1
1
2 PR Session
Last completed ratio (median)
Infusions earned (2 h)
a
2 PR Session
adolescent vehicle-pretreated adolescent nicotine-pretreated
adult vehicle-pretreated adult nicotine-pretreated
Figure 25. Reinforcing efficacy of nicotine in rats pretreated with nicotine during adolescence or adulthood. Mean (±SEM) number of nicotine infusions earned (bars) and median breakpoints (lines) achieved in 2 h operant sessions a progressive ratio reinforcement schedule in adult male rats pretreated with vehicle or nicotine (0.4 mg/kg, s.c., x 10 d) during (a) adolescence and (b) adulthood. n=10 per group. *p < .05 compared to vehicle-pretreated controls.
258
