Neurochemical Consequences of Dysphoric State ... - Springer Link

Neurochem Res (2008) 33:204–219 DOI 10.1007/s11064-007-9409-7

OVERVIEW

Neurochemical Consequences of Dysphoric State During Amphetamine Withdrawal in Animal Models: A Review Junichi Kitanaka Æ Nobue Kitanaka Æ Motohiko Takemura

Accepted: 7 June 2007 / Published online: 29 June 2007 Springer Science+Business Media, LLC 2007

Abstract Chronic abuse of amphetamines, such as d-amphetamine (AMPH) and d-methamphetamine, results in psychological dependence, a condition in which the drug produces a feeling of satisfaction and a drive that requires periodic or continuous administration of the drug to produce overwhelming pleasure or to avoid discomfort such as dysphoria. The dysphoric state of AMPH withdrawal has been recognized as depressive syndromes, such as anhedonia, depression, anxiety, and social inhibition, in early drug abstinence. Medication for treatment of the dysphoric state is important for AMPH abusers to avoid impulsive self-injurious behavior or acts that are committed with unconscious or uncontrolled suicidal ideation. However, successful treatments for AMPH withdrawal remain elusive, since the exact molecular basis of the expression of dysphoria has not been fully elucidated. This review focuses on the molecular aspects of AMPH withdrawal as indexed by neurochemical parameters under a variety of injection regimens (for example, levels of brain monoamines and their metabolites, and c-aminobutyric acid, expression of genes and proteins involved in neuronal activity, and monoamine metabolism and availability) in rodent models which exhibit significant phenotypic features relevant to the syndromes of AMPH withdrawal in humans. Keywords Amphetamine withdrawal Dysphoria Monoaminergic transmission Gene expression Treatment regimen Animal model

J. Kitanaka (&) N. Kitanaka M. Takemura Department of Pharmacology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan e-mail: [email protected]

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Introduction As psychotomimetic agents, amphetamines, such as damphetamine (AMPH) and d-methamphetamine (METH), cause a massive release of dopamine from the presynaptic terminal into the synaptic cleft in the brain [1–5]. The mesolimbic dopamine reward system, activated by aberrant levels of released dopamine, exerts a motivation to seek drugs (for reviews, see Refs. [6–9]). When taken at relatively lower doses, amphetamines cause mood enhancement, such as experiences of euphoria, increased alertness, a sense of self-confidence, and suppression of fatigue [10]. Development of tolerance to mood enhancement increases the intake frequency and dose of the drug in AMPH abusers [11]. Repeated drug use causes dysregulation of the brain reward system that progressively increases compulsive and uncontrolled drug intake [6, 12, 13]. A chronic, higher-dose, multiple daily administration pattern (‘‘binge’’) of amphetamines finally culminates in amphetamine psychosis with psychiatric sequelae (paranoia, delusions, and hallucinations) and abnormal behavior clinically undistinguishable from that of paranoid schizophrenia [14–17]. Drug-induced mood enhancement is often followed by a period during which the mood state is opposite that first experienced when the drug is withdrawn [18]. In some cases, avoidance of the state in dysphoric withdrawal might motivate AMPH abusers to continue to use the drug [6, 12, 14]. Dysphoric state of AMPH withdrawal has been recognized as depressive syndromes, such as anhedonia, depression, anxiety, and social inhibition, in early drug abstinence [12, 19]. A core manifestation of depression is anhedonia, that is, a diminished interest in or pleasure from rewarding stimuli. The depressive state observed in AMPH withdrawal resembles that of major depressive disorder

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[20]. On the basis of epidemiological studies, the rate of depression among AMPH abusers (and vice versa) is substantially higher than among the general population [21– 23]. Watson et al. [24] reported that depression in humans evaluated by the Hamilton Rating Scale for Depression peaked 2–3 days after the last dose of AMPH and persisted for 4 days of drug abstinence. In one case under a followup study [24], the subject suffered persistent depression for several months. Depression-related symptoms including inactivity, fatigue, and anhedonia were marked in the first week of METH abstinence among METH-dependent individuals as indexed by scores via the Beck Depression Inventory II [25]. It was reported in 2000 that 49.4% of self-reported METH-dependent arrestees in a US sample had thoughts of suicide [26]. Medication for the treatment of serious depression is therefore important for AMPH abusers to prevent averse outcomes, including impulsive self-injurious behavior or acts that are committed with unconscious or uncontrolled suicidal ideation. Indeed, there are several successful trials (with very limited benefits) regarding treatments with antidepressants such as mirtazapine, reboxetine, fluoxetine, and imipramine for AMPH abuse [27–30], although successful treatments for all AMPH abusers remain elusive [31, 32]. The putative molecular changes during withdrawal period are thought to reflect neuroadaptive processes that oppose the primary actions of amphetamines in the central nervous system (CNS) in an attempt to maintain homeostasis, which is often expressed long after the drug has been cleared from the body [12, 33]. To recover CNS homeostasis from psychological dependence, drug-induced dopaminergic neuronal excitation should be suppressed by mechanisms involved in the inhibition of positive symptoms. Based on preclinical and clinical observations, depletion of brain monoamines, especially serotonin (5– hydroxytryptamine, 5–HT) and norepinephrine, causes depression [34, 35]. The depressive state expressed from an early stage of drug withdrawal might be one of the candidate mechanisms. In AMPH withdrawal, such monoamine depletion also likely causes negative symptoms which suppress the excitation of dopaminergic tone [16], because of similarities between the depressive symptoms of mood disorders and of state in AMPH withdrawal [20]. However, it is difficult to study these molecular mechanisms in humans. Therefore, there has been growing concern about the relevance of valid and reliable animal models which express behavioral and neurochemical consequences of state in AMPH withdrawal to unravel the molecular mechanisms. It has proven very difficult to model all symptoms of AMPH withdrawal in humans using one animal model (for example, see Refs. [36–38]). In addition, it is well recognized that the designs of drug treatment (dose, route, and number of injections, duration

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between injections, and time of behavioral assessment relative to drug exposure) are important factors determining the subsequent different behavioral effects in rodents [39–42]. What would an invaluable animal model of dysphoric state in AMPH withdrawal look like? To explore this question, this paper is intended to review neurochemical consequences (for example, levels of brain monoamines and their metabolites and c-aminobutyric acid (GABA), genes such as fos/jun family members, and enzyme activities contributing to monoamine metabolism) of AMPH withdrawal in rodent models using a variety of experimental procedures, which show significant phenotypic features related to the syndromes of AMPH withdrawal in humans. We will discuss the state of withdrawal from amphetamines, but not cocaine, in animal models, because of their intrinsic different pharmacological properties. Cocaine solely blocks the activity of the dopamine transporter (DAT) located in presynaptic plasma membranes, while AMPH targets include DAT, the vesicular monoamine transporter-2 (VMAT-2) located in vesicular membranes, and the monoamine oxidase (MAO) isozymes (MAO-A and MAO-B) located in mitochondrial outer membranes [4, 5]. VMAT-2 is a neuronal protein responsible for transporting cytoplasmic monoamines into synaptic vesicles for storage and release, and MAO isozymes catalyze the oxidative deamination of monoamines. Readers interested in more focused reviews of animal models for cocaine withdrawal and addiction are invited to refer to the following articles [18, 43–47]. Both AMPH and METH will be mentioned in this review as drugs with equivalent pharmacological properties because of their chemical structures similar to each other. The term ‘‘withdrawal’’ refers to the absence of AMPH/METH throughout this review.

Design of drug treatments for significant behavioral consequences of AMPH withdrawal To investigate the neurochemical aspects of state in AMPH withdrawal, an experimental design is necessary which should promise to induce significant changes in the behavioral parameters relevant to symptoms of AMPH withdrawal in rodents. In this section, we will summarize published designs of drug treatments which result in significant behavioral consequences of state of AMPH withdrawal in rodents. Open field behavior Rats pretreated with an escalating injection protocol of AMPH (1–10 mg/kg, i.p., for 4 days to 6 weeks) exhib-

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ited decreased spontaneous locomotion after 1–12 days of AMPH abstinence in novel and habituated experimental contexts [41, 48, 49]. Decreased repetitive movement was also observed in rats pretreated with a fixed-dose injection regimen of AMPH (7.5 mg/kg ·2 injections per day for 2 weeks) 24–54 h after final AMPH treatment [50]. In contrast, mice pretreated with AMPH (5 mg/kg ·2 injections per day for 5 consecutive days) exhibited no change in locomotor activity in a novel environment on day 1 of withdrawal [36], suggesting that observed effects on locomotion during AMPH withdrawal may depend on the species used. Quantitative analysis of open field behavior except locomotion was reported by Lynch and Leonard using rats [51]; rearing and grooming significantly decreased and increased, respectively, 2 days after oral AMPH treatment (50–200 mg/l for 3 weeks). The decreased rearing behavior persisted for 6 days of AMPH abstinence. Treatment of the rats for 4 days with the antidepressant mianserin significantly reversed the negative symptom-like effect on rearing and grooming, suggesting that postdrug depression may be associated with a significant change of rearing and grooming.

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Latent inhibition The expression of latent inhibition (LI) has been used to assess attention deficit during AMPH withdrawal. LI refers to the observation that repeated exposure to stimuli without consequence impedes the formation of subsequent associations with those stimuli [56]. In the LI paradigm, repeated treatment with AMPH disrupts the process of learning to ignore irrelevant stimuli. Rats pretreated with an escalating injection regimen of AMPH (1–5 mg/kg, i.p. ·3 injections for 6 days) lost the acquisition of LI on days 4–16 of AMPH withdrawal [57, 58]. The elimination of LI was also observed in rats pretreated with 1.5 mg/kg of AMPH per day for 2 weeks after 1 day of drug abstinence [59]. Prepulse inhibition Recent studies indicate the relevance of the prepulse inhibition (PPI) paradigm for assessment of an aspect of cognitive dysfunction in AMPH withdrawal [49, 60]. In these reports, an escalating dose injection (1–10 mg/kg, i.p., ·3 injections per day for 4 days, or 1–8 mg/kg, i.p., ·3 injections per day for 6 days) effectively disrupted PPI in rats on days 4–55 of withdrawal.

Object recognition Intracranial self-stimulation A novelty preference task of object recognition has been used as an index of cognitive aspects of AMPH withdrawal. This assessment is thought to reflect evidence of cognitive dysfunction associated with the depressive state in AMPH withdrawal in humans [52]. Schreiber et al. [53] reported that rats treated with 5 mg/kg of AMPH for 8 days showed a reduced reaction to novelty (a felt doll) after 1–day AMPH abstinence, compared with control animals, without a decrease in locomotor activity. Impaired object recognition was also reported after 7–day AMPH abstinence in rats (3 and 2.6 mg/kg for males and females, respectively, for 10 alternate days) using two different types of objects (soda cans and plastic bottles) [54]. A neurotoxic dose regimen (four METH (4 mg/kg) injections within a day at 2-h interval) induced impairment of object recognition (light bulbs and a hook) in rats [55]. In line with these experiments, it is suggested that repeated AMPH administration may impair object recognition processes during AMPH withdrawal in rats. However, there is a possibility that the reduced reaction to novelty (for example, Ref. [53]) may be associated with fear and/or reduced impulsivity, but not with cognitive dysfunction. An obvious remaining question is to reveal whether both cognitivetype symptoms, such as suicide ideation in AMPH abusers and a decreased novelty preference in animals, during AMPH withdrawal would have substantially identical molecular mechanisms.

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Electrical stimulation to certain brain sites of rodents possesses reinforcing properties [61], which are thought to be reduced under anhedonia of drug withdrawal. The state of AMPH withdrawal is most commonly evaluated by a reduction in the animal’s response to rewarding electrical intracranial self-stimulation (ICSS) in early AMPH abstinence, because of its high sensitivity to depressant effects, compared with other behavioral measures [36, 62–70]. The ICSS procedure requires surgery in which bipolar electrodes are implanted into the medial forebrain bundle at the level of the rodents’ posterior lateral hypothalamus, where electric stimulation provides an index of trans-synaptic modulation of activity in limbic areas, such as the nucleus accumbens (NAc) [36, 62, 63, 66–71] (but see Refs. [64, 65], who implanted the electrodes into the substantia nigra). In earlier reports, changes in ICSS rates have been measured, exhibiting a significant decrease after 1–4-day AMPH abstinence in rats [62–64, 69] and in mice [36]. The significant decrease in ICSS rates postulates an ‘‘anhedonic’’ response to brain stimulation in rodents. The timecourse of the change in ICSS rates was similar to that of the depressive state observed in humans [24]. Early ICSS rate measures were replaced with reinforcement current thresholds in later experiments [66–68, 70]. The discretetrial current-threshold procedure has been shown to provide a more sensitive threshold measure of drug-induced chan-

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ges in reward function [71, 72]. Increased ICSS thresholds reflect the depressive anhedonia of AMPH withdrawal, since decreases in ICSS thresholds were associated with increases in immobility time in the forced swim test (rat) and tail suspension test (mouse) [36, 70] (please note: Cryan et al. [70] delivered AMPH to rats via osmotic minipumps inserted subcutaneously). In addition, the depressive ICSS response was reversed by the antidepressant imipramine [65]. Changes in ICSS thresholds are strongly associated with the drug-treatment regimen such as the time interval between successive injections of the drug [42]. In line with these observations, to obtain ICSS threshold elevations in rats during the postdrug period, daily AMPH administration (an escalating injection regimen ranging between 1 and 12 mg/kg ·2–3 injections per day for 4 days–6 weeks or a fixed-dose injection regimen ranging between 2.5 and 10 mg/kg ·2–3 injections per day for 5–10 days) is required followed by a withdrawal period of 1–5 days. Notably, repeated drug challenges at 5-day intervals decreased ICSS thresholds after drug injection and diminished threshold elevations during the postdrug period, which is conceivably associated with the development of reverse tolerance or sensitization to the drug [42]. Other measures Several other measures have been applied successfully to evaluate behavioral changes in AMPH-withdrawn rats. A significant decrease in several motivational components of sexual behavior in rats 12 h after an escalating dose injection regimen (1–12 mg/kg, i.p., ·3 injections per day for 4 days) was reported by Barr et al. [73], whereas Pezze et al. [74] showed increased conditioned freezing in response to a tone associated with electric foot-shock in rats exposed to conditioning of tone-shock association on day 4 of AMPH withdrawal after an escalating dosage of AMPH (1–5 mg/kg, i.p., ·3 injections per day for 6 days). Russig et al. [75] and Peterson et al. [76] expected to observe changes in learning and memory during AMPH withdrawal. Russig et al. [75] trained rats to escape from water to a platform in the Morris water maze. The rats were then treated with an escalating dosage of AMPH (1–5 mg/ kg, i.p., ·3 injections per day for 6 days). The animals were trained again in the water maze with the platform positioned in the opposite direction compared with the first training session. Acquisition of the ‘‘reversal of spatial learning’’ was evaluated as indexed by time spent in the area with the newly fixed platform. Under this experimental design, Russig et al. [75] showed that enhanced reversal learning 4–5 days after treatment was apparent in both AMPH- and saline-treated rats, but was more prominent in the AMPH group. They suggested that putative behavioral changes related to state in AMPH withdrawal

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may diminish proactive interference whereby what has been learned previously impedes subsequent learning. Peterson et al. [76], utilizing the differential reinforcement of low rates of responding operant conditioning tasks, showed a decreased percentage of training efficacy in rats trained to inhibit a nose poke response for 30 s before subsequent repeated AMPH injections (5 mg/kg, i.p., ·1 injection per day for 5 days; 6–8-day withdrawal). AMPH injection regimen promising the expression of symptoms of AMPH withdrawal Overall, on the basis of observations of several behavioral paradigms relevant to AMPH withdrawal, rats pretreated with an escalating injection regimen (1–12 mg/kg, i.p., ·2– 3 injections per day for 4 days–6 weeks) or a fixed-dose injection regimen (1.5–10 mg/kg, i.p., ·1–3 injections per day for 5 days–2 weeks) promised to exhibit the behavioral aspects of AMPH withdrawal. These rats should also be used to investigate the neurochemical aspects of AMPH withdrawal. The required postdrug period varies from 12 h (as indexed by ICSS, Barr et al. [69]) to 55 days (as indexed by PPI, Peleg-Raibstein et al. [60]). Few reports are available regarding behavioral and neurochemical aspects of AMPH withdrawal using mice (but see Refs. [36, 70]).

Neurochemical consequences of AMPH withdrawal in rodent models Significant changes in neurochemical parameters during AMPH withdrawal are summarized in Table 1. Some of the injection regimens included in Table 1 closely resemble but do not exactly fit the proposed regimens relevant to significant rodent behavioral changes associated with the syndromes of AMPH withdrawal in humans (discussed above). Nevertheless, neurochemical data obtained under these treatment regimens were retained in this review because of their importance. Postmortem brain tissue levels of dopamine and metabolites after drug abstinence period It is well documented that AMPH-induced elevation of mesolimbic and mesocortical dopaminergic tone causes an augmentation in motor activity in rodents [9, 77, 78]. It would be expected to observe reduced locomotor activity during AMPH withdrawal (especially in rats) via a mechanism whereby dopaminergic tone is suppressed. Tissue levels of dopamine were reduced in the prefrontal cortex (PFC), striatum, and posterior caudate nucleus after 12, 36 h, and 5 days of AMPH abstinence, respectively, in rats treated with a fixed-dose regimen of AMPH (7.5 mg/

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Table I Significant changes in neurochemical parameters during withdrawal from chronic amphetamine/methamphetamine administration in rodents Measure

Speciesa and drug treatment schedule

Postdrug period

Effect

Reference

83

Postmortem brain tissue monoamine and GABA levels after drug abstinence period Rat, METH, 2.5–15 mg/kg · 5/dy, s.c., 1 wkc

18 h

Decrease (Str)

Rat, AMPH, 7.5 mg/kg · 2/dy, i.p., 10 dy

5 dy

Decrease (PC)

79


5 dy

Increase (NAc)

79

Rat, AMPH, 7.5 mg/kg · 2/dy, i.p., 2 wk

36 h

Decrease (Str)

80


12 h

Decrease (PFC)

80

Rat, AMPH, 1–5 mg/kg · 3/dy, i.p., 6 dy

55 dy

Decrease (AMY)

60


55 dy

Decrease (CPu)

60

HVA

Rat, METH, 2.5–15 mg/kg · 5/dy, s.c., 1 wkc

18 h

Increase (Str)

83

DOPAC

Rat*, AMPH, 1–10 mg/kg · 2/dy, i.p., 6 wkb

12 dy

Increase (Str)

41

Rat*, AMPH, 1–10 mg/kg · 2/dy, i.p., 6 wkb Rat, AMPH, 7.5 mg/kg · 2/dy, i.p., 10 dy

12 dy 5 dy

Increase (NAc) Decrease (PC)

41 79


5 dy

Increase (NAc)

79

Rat, d,l-AMPH, 3 mg/kg, p.o., 9 mo

3 dy

Decrease (Cb)

83

Rat, AMPH, 200 mg/l, p.o., 3 wk

12 h

Decrease (Str)

94


12 h

Decrease (Cx)

94

Dopamine

5-HT

Rat, METH, 2.5–15 mg/kg · 5/dy, s.c., 1 wk

5-HIAA

c

18 h

Decrease (Str)

83


12 h

Decrease (PFC)

80


55 dy

Decrease (CPu)

60


55 dy

Decrease (CPu)

60


12 h

Increase (Str)

94


12 h

Increase (Cx)

94

Rat, METH, 2.5–15 mg/kg · 5/dy, s.c., 1 wk

c

18 h

Decrease (Str)

83


12 h

Decrease (PFC)

80

Rat, d,l-AMPH, 3 mg/kg, p.o., 9 mo

3 dy

Decrease (Cb)

93

Rat, AMPH, 200 mg/l, p.o., 3 wk Rat, AMPH, 200 mg/l, p.o., 3 wk

12 h 12 h

Decrease (Str) Decrease (Cx)

94 94

Rat*, AMPH, 1–10 mg/kg · 2/dy, i.p., 6 wkb

3–7 dy

Decrease (Hyp)

48


12 h

Decrease (PFC)

80

MHPG


2 dy

Decrease (Whole)

101

GABA

Rat, AMPH, 50–200 mg/l, p.o., 2 wk

12–36 h

Decrease (Str)

102


12–36 h

Decrease (Stem)

102


12 h and 2–7 dy

Increase (AMY)

102


1–5 dy

Decrease (VStr)

104


12 h and 7 dy

Decrease (VStr)

105

Rat, METH, 2 mg/kg · 1/dy, i.p., 10 dy

1 dy

Decrease (NAcSh)

90

Rat, AMPH, 2.5 mg/kg · 1/dy, s.c., 5 dy

1 wk

Increase (VTA)

106

Rat, AMPH, 2.5 mg/kg · 1/dy, s.c., 5 dy

1 wk

Increase (SN)

106

Rat, AMPH, 5 mg/kg · 1/dy, i.p., 5 dy

3 and 14 dy

Increase (VTA)

107

Rat, AMPH, 5 mg/kg · 1/dy, i.p., 5 dy Rat, AMPH, 7.5 mg/kg · 2/dy, i.p., 2 wk

3 dy 36 h

Increase (SN) Decrease (M/p)

107 86


3 dy

Increase (tVS)

107

NE

Extracellular monoamine concentrations after drug abstinence period Dopamine

Postmortem brain tissue mRNA expression levels after drug abstinence period DAT

VMAT-2

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Table I continued Measure

Speciesa and drug treatment schedule

Postdrug period

Effect

Reference

c-fos


12–54 h

Decrease (PFC)

80

Rat, AMPH, 0.5 mg/kg · 1/dy, i.v., 7 dy

10–12 dy

Increase (DStr)

103


10–12 dy

Increase (STN)

103


10–12 dy

Decrease (CeA)

103


10–12 dy

Increase (NAcSh)

103

fos-B


12–54 h

Decrease (PFC)

80

jun-B


12–54 h

Decrease (PFC)

80

NMDAR1


2 wk

Decrease (NAc)

111


2 wk

Decrease (PFC)

111


1 wk

Increase (NAc)

113

connexin 36

Postmortem brain tissue protein expression levels or activity after drug abstinence period DAT

Rat, METH, 2 mg/kg · 1/dy, i.p., 10 dy

1 dy

Increase (NAc)

90

FosB


4 dy

Increase (NAcSh)

115

MAO activity

NMDAR1 syntaxin 1 synaptophysin


4 dy

Increase (BLA)

115

Guinea pig, METH, 6 mg/kg · 1/dy, s.c., 20–70 dy Guinea pig, METH, 6 mg/kg · 1/dy, s.c., 20–70 dy

50 h 1–3 wk

Decrease (Cx) Increase (Cx)

91 92

Mouse, METH, 5 mg/kg · 1/dy, i.p., 4 wk

1–3 wk

Increase (Whole)

92


2 wk

Decrease (NAc)

111


2 wk

Decrease (SN)

111

Rat, AMPH, 1.5 mg/kg · 1/alt dy, i.p., 5 dy

2 wk

Decrease (NAcCo)

118


2 wk

Increase (NAcSh)

118


2 wk

Decrease (NAcCo)

118

This table shows the published amphetamine/methamphetamine withdrawal effects (more than 12 h withdrawal from multiple injections of the drug) on neurochemical parameters in rodents. The term ‘‘withdrawal’’ here refers to the absence of amphetamine/methamphetamine. The drug dose ranges indicate that escalating doses within the ranges were injected to animals. Abbreviations: alt dy, alternate days; AMPH, d-amphetamine unless otherwise indicated; AMY, amygdala; BLA, basolateral amygdala; Cb, cerebellum; CeA, central nucleus of amygdala; Cx, cerebral cortex; DAT, cocaine-sensitive dopamine transporter; DOPAC, 3,4-dihydroxyphenylacetic acid; DStr, dorsal caudal striatum; dy, day(s); FC, frontal cortex; GABA, c-aminobutyric acid; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine (serotonin); HVA, homovanillic acid; Hyp, hypothalamus; i.p., intraperitoneally; i.v., intravenously; MAO, monoamine oxidase; METH, d-methamphetamine; mo, month(s); MHPG, 3-methoxy-4-hydroxyphenylglycol; M/p, midbrain/pons region, including the ventral tegmental area, substantia nigra pars compacta and locus coeruleus; NAc, nucleus accumbens; NAcCo, nucleus accumbens core; NAcSh, nucleus accumbens shell; NE, norepinephrine; NMDAR1, NMDAR1 subunit of N-methyl-D-aspartate receptor; PC, posterior caudate nucleus; PFC, prefrontal cortex; p.o., orally (in these cases, it is difficult to estimate the exact dose of the drug received, since the drug was ingested with food or water); s.c., subcutaneously; SN, substantia nigra; STN, subthalamic nucleus; Str, striatum; tVS, transitional zone between ventral tegmental area and substantia nigra; VMAT-2, vesicular monoamine transporter-2; VStr, ventral striatum; VTA, ventral tegmental area; wk, week(s). a

Male subjects; asterisks indicate females.

b

Injections were given each weekday, but not on weekends.

c

Injections were given on days 1, 3, 5 and 7

kg, i.p., ·2 injections per day for 10–14 consecutive days) [79, 80]. An escalating injection regimen (1–5 mg/kg or 1– 8 mg/kg of AMPH, i.p., ·3 injections per day for 6 days) also produced a profound and long-lasting reduction of the tissue level of dopamine in the amygdala and caudate putamen in rats on day 55 of AMPH withdrawal [60]. One exception was reported by Swerdlow et al. [79]; tissue dopamine levels significantly increased in the NAc on day 5 of AMPH abstinence (7.5 mg/kg, i.p., ·2 injections per day for 10 days). Also, a significant increase in the levels of dopamine was observed in the olfactory lobes of rats

(2 weeks of AMPH administration via a p.o. route) up to 1 week after the drug treatment regimen, although a significant decrease was evident in some brain regions of the nigrostriatal tract examined [81]. Conclusions drawn by experiments utilizing neurotoxic drug treatment regimens provide us with hints speculating several possible mechanisms whereby the tissue levels of dopamine except in the NAc were reduced during AMPH withdrawal. First, dopaminergic neuronal degeneration is evident following a neurotoxic METH regimen (50 mg/kg, s.c., ·3 injections within 1 day, every 8 h) [82]. This

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neuronal degeneration may be responsible for tissue dopamine decrement in some cases of AMPH/METHwithdrawn rats. Indeed, an escalating, neurotoxic injection regimen (METH dosage from 2.5 to 15 mg/kg, s.c., ·5 injections per day for 4 alternate days) decreased the striatal content of dopamine in rats after 18 h of METH abstinence [83]. Second, there is a possibility that the METH-induced decrease in VMAT-2 activity [84, 85] disrupts the subcellular compartmentation of dopamine, resulting in its enzymatic metabolism and subsequent reduced availability. Also, the expression level of VMAT-2 mRNA was significantly reduced in the midbrain/pons region, including the ventral tegmental area (VTA), substantia nigra pars compacta and locus coeruleus 36 h after AMPH treatment regimen (7.5 mg/kg, i.p., ·2 injections per day for 2 weeks) [86]. Third, the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme responsible for the synthesis of catecholamines, decreased following neurotoxic METH administration (15 mg/kg, s.c., ·4–5 injections every 6 h) in the neostriatum of rats on days 1–30 of withdrawal [87, 88]. Quantitative immunochemical studies demonstrated that a fixed-dose, neurotoxic regimen (20 mg/kg of METH, i.p., ·2 injections per day for 10 consecutive days) produced a long-lasting decrease in TH antibody staining within the neurons of the VTA (as well as in the NAc) on day 60 of METH abstinence [89]. Fourth, enhanced metabolism of dopamine (via the MAO enzyme) may be involved in the decreased tissue levels of dopamine in striatal regions during AMPH withdrawal, leading to the consequent increase of its metabolites (discussed below). It should be noted that, since these drug injection regimens were neurotoxic to rats [83–85, 87–89], further studies are required to investigate whether treatment regimens resulting in AMPH withdrawal can also induce long-lasting molecular changes relevant to dopaminergic neurotoxicity associated with reduced functions of VMAT-2 and TH. Broom and Yamamoto [90] observed a significant increase in DAT immunoreactivity during METH withdrawal (2 mg/kg, i.p., ·one injection per day for 10 days; 1 day of withdrawal) in the NAc. This phenomenon may account for increased tissue levels of dopamine in the NAc during AMPH withdrawal [79], resulting in a decrease in extracellular dopamine concentrations [90] (discussed below). In this treatment regimen, TH activity may not decrease in the NAc, since Trulson et al. [89] used a higher drug dosage, ten times that of Broom and Yamamoto [90]. Regarding dopamine metabolites, levels of 3,4-dihydroxypenylacetic acid (DOPAC) and homovanillic acid (HVA) significantly increased in regions of the striatum and/or NAc during AMPH withdrawal after both fixeddose and escalating injection regimens [41, 79, 83]. In contrast to this, a decrease in the tissue DOPAC level was

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observed in the posterior caudate nucleus during AMPH withdrawal [79]. Enhanced metabolism of dopamine in striatal regions is one of the possible mechanisms which can account for observations during AMPH withdrawal. METH-induced disruption of VMAT-2 function [84, 85] may prompt sequential clearance of non-available dopamine from the brain, resulting in an increase in the tissue levels of DOPAC and HVA. The simplest and most considerable explanation may be the enhancement of MAO activity during AMPH withdrawal, while amphetamines are weak but reversible MAO inhibitors in vitro (for review, see Ref. [78]). In guinea pigs, cortical MAO activity was reduced after 50 h of METH abstinence, and in turn, enhanced at 1–3 weeks of withdrawal [91] (see Table 1 for drug injection regimen). The enhancement period was suggested to be an adaptive phenomenon of MAO stimulation by METH [91]. Enhanced MAO activity was also reported in mice after 1–3 weeks of METH abstinence utilizing a relatively neurotoxic injection regimen (5 mg/ kg, i.p., ·one injection for 4 weeks) [92] (Table 1). Although this phenomenon should be confirmed by further studies regarding the up-regulation of MAO genes and proteins, increased tissue levels of dopamine metabolites may reduce the dopaminergic tone, resulting in the dysphoric state of AMPH withdrawal. Postmortem brain tissue levels of 5-HT and the metabolite after drug abstinence period The involvement of 5-HTergic pathways in induction of the dysphoric state of AMPH withdrawal may be apparent, because a reduction in 5-HTergic tone causes depression [34, 35]. Tissue levels of 5-HT significantly decreased in the cerebellum, striatum, cerebral cortex, and PFC after 12 h-3 days of AMPH/METH abstinence [80, 83, 93, 94]. It is noted that the drug treatment regimens, except that of Persico et al. [80], did not completely fit the proposed regimens promising behavioral changes associated with symptoms of AMPH withdrawal. The decrease in 5-HT levels was visualized in the parietal cortex, striatum, dorsal hippocampus, and lateral entorhinal area of rats 4 h after a single administration of METH (15 and 100 mg/kg, s.c.) by immunocytochemical studies utilizing rabbit antiserum directed against 5-HT [95]. The activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme responsible for the synthesis of 5-HT, decreased on days 1–30 of withdrawal after neurotoxic METH administration (15 mg/kg, s.c., ·4–5 injections, every 6 h) in the neostriatum and NAc of rats [87, 88]. The decrease in TPH activity occurred sooner and was more pronounced compared with TH activity [87, 88]. Also, even a single administration of METH (10 mg/kg, s.c.) reduced neostriatal TPH activity by 53–26% after 3–12 h of drug challenge, while the

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simultaneous measurement of TH activity remained unchanged [96], suggesting that synthesis of 5-HT may be more sensitive to METH than synthesis of dopamine. Therefore, it is likely that the proposed regimens (nonneurotoxic) promising behavioral changes associated with symptoms of AMPH withdrawal may reduce the tissue levels of 5-HT via suppression of TPH activity. Contradictory results have been reported regarding changes of the tissue levels of 5-hydroxyindoleacetic acid (5-HIAA), a 5-HT metabolite, in striatal and cortical regions during AMPH withdrawal. Tonge [94] showed a significant increase in 5-HIAA levels after 12 h of AMPH abstinence, while decreased levels were observed after 12– 18 h of AMPH abstinence by Schmidt et al. [83] and Persico et al. [80]. Provided that MAO enzyme activity is enhanced during AMPH withdrawal (as discussed above), a larger amount of brain 5-HT may be exposed to the enhanced MAO metabolic pathway during AMPH withdrawal than under normal conditions, resulting in an increase in 5-HIAA levels, as reported by Tonge [94]. It is noted that only Tonge [94] used the p.o. administration route. In this route, it is difficult to estimate the exact dose of the drug that animals received, since the drug was taken into the animal with a non-defined intake of food or water. Obviously, the 5-HTergic system is more sensitive to single or repeated METH than the dopaminergic system in terms of amine synthesis [87, 88, 96]. The same conclusion as that of Gibb’s group was drawn by Ricaurte et al. [97] in terms of amine synthesis, utilizing another neurotoxic METH treatment regimen (25 and 100 mg/kg/day, s.c., ·2 injections for 4 days). In line with these observations, the size of the 5-HT pool available as a neurotransmitter may be reduced more than that of dopamine during AMPH withdrawal in terms of amine synthesis (i.e., vulnerability of TH versus TPH to AMPH). Provided that this contribution to the 5-HIAA level (i.e., decrease) is larger than that of upregulation of the MAO metabolic pathway (i.e., increase) after drug abstinence, tissue levels of 5-HIAA may be reduced compared with control animals during AMPH withdrawal, as reported by Schmidt et al. [83] and Persico et al. [80]. This should be clarified by further studies. Postmortem brain tissue levels of norepinephrine and the metabolite after drug abstinence period The involvement of the norepinephrinergic system in mood disorders has been verified by the successful treatment of depressed patients with antidepressants including mirtazapine (an antidepressant that affects both 5-HT and norepinephrine systems) and desipramine (a norepinephrine reuptake inhibitor). There is a possibility that decreased norepinephrinergic tone may induce the dysphoric state of AMPH withdrawal. This possibility is supported by evi-

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dence that the urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) decreased after AMPH withdrawal in humans [24, 98]. Urinary MHPG excretion serves as an index of brain norepinephrine synthesis and metabolism [99, 100]. A significant decrease in the tissue levels of norepinephrine was observed in the PFC and hypothalamus during AMPH withdrawal utilizing both fixed-dose and escalating injection regimens [48, 80] (Table 1) as well as in the cerebellum and cortex under the p.o. route administration protocol [93, 94]. Up-regulation of the MAO metabolic pathway after drug treatment could not account for this phenomenon, since MHPG levels also significantly decreased (Table 1; discussed below). It has not been demonstrated whether amphetamines cause the degeneration of norepinephrinergic axon terminals, a phenomenon which should be accompanied by decreased norepinephrine nerve markers such as dopamine b-hydroxylase (the ratelimiting enzyme of norepinephrine synthesis) and norepinephrine transporter. As expected on the basis of human observations [24, 98], an escalating injection regimen (AMPH, 1–12 mg/kg, i.p., ·3 injections per day for 4 days) caused a significant decrease in the MHPG level of the rat whole brain at day 2 of AMPH withdrawal [101]. The size of the norepinephrine pool available as a neurotransmitter may be reduced more than that of dopamine during AMPH withdrawal. No significant change in brain MHPG levels was observed 2 h after the fixed-dose injection regimen (5 mg/kg, i.p., ·2 injections per day for 10 days) [101], suggesting that the injection regimen may influence norepinephrine metabolism during AMPH withdrawal. Postmortem brain tissue levels of GABA after drug abstinence period Few studies regarding brain GABA levels during AMPH withdrawal have been reported. A significant increase in tissue GABA levels (which may reflect the reduction of GABA availability) was observed in the amygdala 12 h and 2–7 days after p.o. AMPH treatment regimen, while a significant decrease in the tissue level was evident in the brain stem and striatum 12–36 h after AMPH abstinence [102]. A significant decrease in the expression levels of the c-fos gene was observed in the central nucleus of the amygdala during AMPH withdrawal [103], suggesting reduced neuronal activity in the amygdala. These neurochemical amygdalar responses to AMPH (i.e., increased tissue GABA level and decreased c-fos expression) may reduce responses to external stimuli, since reduced GABA release from the amygdala ceases the inhibition of GABAergic projections from the preoptic area to the hypothalamic paraventricular nucleus, resulting in the inhibition of

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corticotropin-releasing hormone release from the paraventricular nucleus. It has not been demonstrated that the decrease in the striatal GABA level during AMPH withdrawal [102] reflects the degeneration of GABAergic neurons. Provided that GABAergic neuronal damage is evident, the release of GABA may decrease. Reduced GABA release from the striatum ceases the inhibition of GABAergic projections from the internal segment of the globus pallidus to the thalamus, resulting in the suppression of thalamic functions including excitation of the cortex and striatum. Regardless, few previous studies have demonstrated the close relationship between the GABAergic system and the development of symptoms in AMPH withdrawal functionally. To enhance understanding of the neurochemical aspects of the mechanism whereby the state of AMPH withdrawal is induced, studies regarding the molecular basis of changes in tissue GABA levels during AMPH withdrawal should also be performed. Extracellular dopamine concentration after drug abstinence period In the rat ventral striatum, in vivo microdialysis revealed that basal levels of extracellular dopamine concentrations were significantly reduced during a 12-h and 1–7-day AMPH withdrawal period (1.5 mg/kg, i.p., ·2 injections per day for 14–16 days), suggesting that this neurochemical change may be associated with the aversive subjective symptoms of AMPH withdrawal [104, 105]. As mentioned above, tissue dopamine levels in the NAc, the major part of the ventral striatum, significantly increased during AMPH withdrawal [79]. There are two possibilities which can account for the observations of these studies [79, 104, 105]. First, the ability of mesolimbic dopamine release may be reduced after drug abstinence, resulting in the accumulation of non-available dopamine in the ventral striatum. The long-term dysfunction (or down-regulation) of DAT after drug abstinence is a possible molecular basis of this phenomenon. Second, in contrast to the first possibility, the long-term up-regulation of DAT function after drug abstinence is an alternative candidate. The second possibility is more likely to account for the change in dopamine levels during AMPH withdrawal, because Broom and Yamamoto [90] demonstrated that a fixed-dose injection regimen (METH, 2 mg/kg, i.p., ·one injection per day for 10 days) reduced the basal level of extracellular dopamine concentrations and that increased DAT immunoreactivity in the NAc shell, suggesting that increased DAT-mediated regulation of extracellular dopamine concentrations may account for the reduction in extracellular dopamine concentrations in the NAc. An increase in DAT mRNA expression during AMPH withdrawal has been reported

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utilizing several drug treatment regimens [106, 107], suggesting that up-regulation of DAT protein expression may occur in specific brain regions during AMPH withdrawal (discussed below). Postmortem brain tissue mRNA expression levels after drug abstinence period DAT The up-regulation of DAT mRNA expression was observed in the VTA and substantia nigra after 1 week of AMPH treatment regimen in rats (2.5 mg/kg, s.c., ·one injection per day for 5 days) [106]. The same conclusion as that of Shilling et al. [106] was drawn utilizing a similar fixeddose injection regimen (5 mg/kg, i.p., ·one injection per day for 5 days; 3–14 days of drug abstinence) [107]. However, Persico et al. [86] observed no change in DAT mRNA expression during AMPH withdrawal (7.5 mg/kg, i.p., ·2 injections per day for 2 weeks; 36 h of drug abstinence) in the midbrain/pons region including the VTA, substantia nigra pars compacta and locus coeruleus. It is likely that that these discrepancies in the changes in DAT mRNA expression can be explained by differences in the type of tissue dissection method and the duration of withdrawal. Provided that up-regulation of the expression of DAT mRNA during AMPH withdrawal is evident in the ventral striatum, this phenomenon can account for the enhancement of DAT function, resulting in a decrease in extracellular dopamine concentrations in the ventral striatum [90, 104, 105]. Regardless, no previous studies have related significant changes in the expression of DAT mRNA in the ventral striatum during AMPH withdrawal. VMAT-2 Normal VMAT-2 function is necessary to maintain proper dopamine compartmentation and its concentrations in dopaminergic neurons. Once impaired, vesicular dopamine transport is disrupted. Acute METH administration decreases VMAT-2 activity [84, 85], suggesting that METH may disrupt the proper dopamine compartmentation in vivo. Persico et al. [86] elucidated a possible mechanism underlying METH-induced decrease in VMAT-2 activity, that is, decreased expression level of VMAT-2 mRNA during AMPH withdrawal. This phenomenon was evident in the midbrain. Results contrary to this were reported in the transitional zone between VTA and substantia nigra by Lu and Wolf [107]. Further studies are required to address whether in vivo VMAT-2 activity actually influences significant changes in the tissue levels of dopamine (and other monoamines) during AMPH withdrawal. The positive correlation between VMAT-2 activity and VMAT-2

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immunoreactivity should be clarified, since it remains unconfirmed that the drug-induced dysfunction of VMAT-2 protein can be attributed to translational, translocational (or trafficking), or post-translocational levels. Fos/jun family genes Induction of immediate-early genes such as the fos/jun family has been investigated as an index of neuronal activation in the CNS. This approach has been applied to identify the types of neurons engaged by amphetamines (for review, see Ref. [108]). Ostrander et al. [103] investigated in detail the changes in c-fos expression levels in various brain regions 10–12 days after a fixed low-dose AMPH treatment regimen via an intravenous route (0.5 mg/kg ·one injection per day for 7 days). As shown in Table 1, brain region-specific changes in c-fos expression were revealed. In particular, significant increases in c-fos expression levels were detected during AMPH withdrawal in the basal ganglia such as the dorsal caudal striatum, NAc shell, and subthalamic nucleus, regions recognized to regulate motor activity. Neuronal activation as indexed by increased c-fos expression may be associated with increased DAT mRNA expression [106, 107] and its immunoreactivity [90], as well as with neuronal potential for augmentation in motor activity, called behavioral sensitization, to a challenge injection of AMPH [103]. A significant decrease in c-fos expression was observed during AMPH withdrawal in the central nucleus of the amygdala [103], a critical region controlling stress and anxiety responses. Reduced neuronal activity in the amygdala predicts reduced responses to external stimuli. Swerdlow et al. [79] reported that decreased plasma adrenocorticotropic hormone (ACTH) was released following restraint stress after a fixed-dose injection regimen. Russig et al. [109] demonstrated long-term (1 month) suppression of ACTH and corticosterone release after an escalating injection regimen in rats (1–10 mg/kg, i.p., ·3 injections per day for 4 days). These phenomena can account for the expression of anhedonic aspects of state in AMPH withdrawal. Regional expression patterns of transcription factor genes, including c-fos, fos-B, jun-B, c-jun, and zif 268, were investigated during AMPH withdrawal [80]. Of the genes investigated, 3 (c-fos, fos-B, and jun-B) significantly decreased 12–54 h after AMPH treatment regimen (7.5 mg/kg, i.p., ·2 injections per day for 2 weeks; this protocol fits the proposed regimens discussed in this review) in the PFC of rats, suggesting that neuronal activity in the region might be reduced. The PFC is one of the regions which receives dopaminergic projections from the VTA and regulates motivation-related behavior [7, 33]. Regarding behavioral aspects, these rats exhibited a

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reduction in repetitive motor activities as indexed by the stereotypy time measured when the animals repeatedly broke the same infrared beam in a novel environment [80]. In the report by Persico et al. [80], they used a commercially available activity monitor to measure automatically the expression of the postdrug stereotypy as indexed by impulsive behavior at the same position in the measurement chamber. The reduced total beam-cut numbers collected from the same infrared beam may not reflect the reduced stereotypy itself, because of lack of a direct behavioral observation. Thus, the reduced impulsivity recorded in a novel environment may not reflect the depressive state of MAPH withdrawal based simply on the idea that reduced locomotion has been related to postdrug state such as anhedonia, while AMPH injection regimen which Persico et al. [80] used fit exactly the proposed regimens promising the expression of state of AMPH withdrawal. Under their treatment regimen, there is no significant difference of the gross locomotor activities between in chronic saline- and AMPH-treated rats up to 1 week of postdrug period. Direct observation using a rating scale may help evaluate properly the behavioral aspects of the depressive state in AMPH withdrawal. NMDAR1 Although few studies regarding brain glutamate levels during AMPH withdrawal have been reported, glutamate transmission has been recognized to be important to induce neuroadaptations toward behavioral sensitization after repeated psychostimulant treatment. Regarding this point, Wolf’s group has extensively investigated chronic AMPHinduced changes in the expressions of mRNAs and the corresponding proteins associated with glutamate transmission, such as glutamate receptors and transporters (for review, see Ref. [110]). They observed a significant decrease in NMDAR1 mRNA, which encodes the NMDAR1 subunit of N-methyl-D-aspartate receptor, in NAc and PFC after 2 weeks (but not 3 days) of repeated AMPH treatment (5 mg/kg, i.p., ·one injection per day for 5 days) [111]. This long-term depression of NMDAR1 mRNA expression correlated with the decrease in the protein expression level in the NAc. These neurochemical alterations in the NAc may account for decreased neuronal excitability, resulting in hypoactivity in rats. Connexin 36 As discussed, the dysphoric state of AMPH withdrawal is considered an adaptive phenomenon which recovers CNS homeostasis from psychological dependence. Neuronal communication appears crucial to develop neuroadaptations for changes in brain functions after long-term drug

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exposure. Alterations of gap junctional communication between adjacent neurons as indexed by dye coupling reflect, at least in part, neuronal communications after repeated AMPH treatment regimen [112]. Regarding the change in the molecular basis of the gap junction structure, a significant increase in mRNA for connexin 36 was observed in the NAc (but not the PFC) of the rats 1 week after repeated AMPH treatment regimen (2.5 mg/kg, i.p., ·one injection per day for 30 days) [113]. Connexin 36 is one of the gene family members which compose a gap junction protein called connexon [114]. The up-regulation of connexin 36 mRNA expression in the NAc was not accompanied by alterations in the protein expression level, suggesting that connexin 36 mRNA and protein may be differentially regulated [113]. It has not been clarified whether this phenomenon correlates directly to the development of neuroadaptation processes during AMPH withdrawal. Regarding dye coupling, Onn and Grace [112] reported a significant increase in the incidence of dye coupling in the NAc and PFC on days 21–28 of AMPH withdrawal (fixed-dose and escalating dose injection regimens; 1–3 mg/kg, i.p., ·one injection per day for 2– 4 weeks), suggesting enhanced synchronization in electrical activity and the exchange of small molecules between linked cells. Postmortem brain tissue protein expression levels or activity after drug abstinence period

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may be enhanced in the basolateral amygdala during AMPH withdrawal. In line with these observations, subregion-specific alterations of neuroadaptation may occur in the amygdaloid body during AMPH withdrawal. No significant changes in tissue monoamine levels were unexpected [115], since the treatment regimen fit the proposed regimens discussed in this review. MAO activity Alterations in MAO enzyme activity significantly influenced tissue levels of monoamines and associated behavior (for review, see Ref. [78]). As discussed above, biphasic changes in MAO activity (initial, short-term decrease and following long-term increase) were evident in the cortical region of guinea pigs after METH withdrawal [91] (Table 1). Regarding long-term increased activity, Egashira and Yamanaka [92] showed similar results to those of Utena et al. [91] using mice, with kinetic results of decreased Km and constant Vmax values. It was not likely that the changes in MAO activity were due to changes in the expression levels of MAO protein because of no significant changes in MAO activity in titrations by clorgyline and selegiline after repeated METH treatment [92]. There have been no reports regarding alterations in the expression levels of mRNAs and proteins for MAO isozymes in rodents during AMPH withdrawal. NMDAR1

DAT As mentioned above (see Postmortem brain tissue levels of dopamine and the metabolites after drug abstinence period), increased DAT immunoreactivity in the NAc [90] can explain increased tissue dopamine levels and decreased extracellular dopamine concentrations during METH withdrawal (Table 1). FosB Protein expression levels of transcription factors have been investigated as a marker of neuronal activation and applied to identify neurons influenced by repeated amphetamines. Murphy et al. [115] demonstrated that the numbers of FosB-positive nuclei significantly increased in the NAc shell and basolateral amygdala of rats on day 4 of AMPH withdrawal, without significantly affecting basal monoamine levels (dopamine and 5-HT and their metabolites) (treatment regimen; 1–5 mg/kg, i.p., ·3 injections per day for 6 days). While the expression levels of the c-fos gene significantly decreased in the central nucleus of the amygdala [103], Murphy’s observations as indexed by FosB immunoreactivity suggested that neuronal activity

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Studies by Lu et al. [111] demonstrated that alterations in NMDAR1 expression were region- and time-dependent at mRNA and protein levels, and that there was no correlation between changes in NMDAR1 mRNA and protein levels. This example as well as the different alterations in the amygdalar expression levels of transcription factors [103, 115] suggest that real-time and more detailed analyses may be required to reveal the exact neurochemical basis of symptoms in AMPH withdrawal. Synaptic terminal proteins Membrane fusion components, including soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) (syntaxin 1, synaptobrevin 2, and synaptosomalassociated protein of 25 kDa), and their major regulatory molecules (synaptotagmin, synaptophysin, and synapsin) constitute SNARE complexes, which regulate vesicle fusion at the presynaptic terminal, resulting in synaptic transmission, and neuronal plasticity [116, 117]. There is one report regarding the change in the expression levels of synaptic terminal proteins associated with neurotransmitter release during AMPH withdrawal. Of the proteins exam-

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ined by Western blotting, the expression levels of syntaxin 1 significantly decreased and increased in the NAc core and shell, respectively, and synaptophysin levels significantly decreased in the NAc core 2 weeks after repeated AMPH treatment regimen (1.5 mg/kg, i.p., ·one injection per day for 5 alternate days) [118]. The up-regulation of syntaxin 1 levels in the NAc shell may be associated with increased neuronal activity engaged by repeated AMPH treatment regimen as indexed by increased expressions of c-fos [103] and FosB [115]. Alterations in the expression levels of SNARE complex members may have functional implications in the induction of symptoms in AMPH withdrawal at the synaptic plasticity level.

Future directions As discussed, both significantly increased and decreased changes in the tissue levels of monoamines and GABA compared with normal levels may cause a reduction of neuronal activity during AMPH withdrawal, leading to dysphoric symptoms, including depression. Treatment with antidepressants during AMPH withdrawal may be effective when decreased (but not increased) extracellular monoamine concentrations (5-HT and/or norepinephrine) are evident. To achieve success in AMPH withdrawal pharmacotherapy, identification of neurochemical abnormalities is definitively required utilizing a valid animal model (for review regarding depressive state in AMPH withdrawal, see Ref. [119]). Species differences as an animal model of state of AMPH withdrawal Rats have been preferentially used in open field experiments during AMPH withdrawal because of their advantages [41, 48–51], compared with mice [36]. Therefore, reliable neurochemical consequences of AMPH withdrawal may be obtained in parallel with corresponding alterations in open field behavior in rats. Mice may be subjected to AMPH withdrawal experiments when changes in ICSS rates are measured [36], similar to rats [62–64, 69]. Decreases in ICSS thresholds in mice were associated with increases in immobility time in the tail suspension test [70]. However, as Cryan et al. mentioned [70], the possible association of decreases in ICSS thresholds with increases in immobility time in the tail suspension test in mice may depend on the drug injection route. Regarding this point, a significant ‘‘decreased’’ immobility time was observed in the tail suspension test when METH (1–2.5 mg/kg, i.p., ·2 injections per day for 10 consecutive days) was administered to naive mice (Kitanaka et al., in preparation). In mice, it is unlikely that dysphoria-like behavior in AMPH

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withdrawal can be induced by the repeated AMPH administration followed by the period ‘‘AMPH withdrawal.’’ Rather, augmented efforts to escape from a severe stressor like tail suspension can be expressed predominantly. Therefore, the species differences as an animal model of state of AMPH withdrawal may not be negligible in terms of the type of behavioral measures and/or the route of drug administration. Are all mRNAs and proteins listed functionally associated with symptoms of AMPH withdrawal? We now have sufficient neurochemical data utilizing rats to allow us to begin to understand which molecule(s) potentially underlie the induction of the state of AMPH withdrawal. One of the initial questions is whether all candidate molecules listed in Table 1 are actually relevant to induction of the negative symptoms in AMPH withdrawal. In ICSS paradigm, drug treatment regimen and the periods of time following the drug withdrawal both determine subsequent phenomena, that is, the state of AMPH withdrawal and behavioral sensitization [42]. Treatment of rats with pergolide and ondansetron, an ergot-derived dopamine agonist and a 5-HT3 receptor antagonist, respectively, during the METH withdrawal period reduced METH-induced behavioral sensitization [120]. In line with these observations, we are aware of a possibility that some of the mRNAs and/or proteins listed may be responsible solely for development of the behavioral sensitization. Alternatively, the candidate molecules discovered within 1 day of postdrug period may participate in common biological pathway(s) toward the subsequent negative symptoms of AMPH withdrawal and the behavioral sensitization. To address this issue, we are approaching a goal of neurochemistry of the symptoms of AMPH withdrawal, utilizing the combined analytical techniques (discussed below). Neurochemistry of the symptoms of AMPH withdrawal Regarding dopamine availability in rats, it is likely that decreased tissue levels of dopamine in brain regions crucial for drug abuse are evident during AMPH withdrawal except in the ventral striatum (especially, the NAc) (Table 1). Drug treatment regimens which induce withdrawal symptoms are generally non-neurotoxic. In neurotoxicity studies, dopaminergic nerve terminal degeneration [82], decrease in TH activity [87, 88], and decrease in VMAT-2 activity [84, 85] were observed after repeated METH treatment. In contrast, these neurochemical alterations have not been reported under the proposed drug treatment regimens promising the expression of behavioral aspects of AMPH withdrawal in rodents. In line with these observations, the exact molecular basis of decreased dopamine

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availability during AMPH withdrawal should be investigated in the future. Alteration in MAO activity largely influences dopamine metabolism and its availability (but not norepinephrine metabolism [101]). Its contribution to the development of AMPH withdrawal should be assessed by studies of enzyme activity (for example, Ref. [91, 92]) and for region- and time-dependent expressions of MAO genes and proteins as well as their molecular conformational alterations. Studies by in situ hybridization histochemistry have realized more detailed analyses of focused postmortem brain regions which were engaged by repeated amphetamines (for example, Ref. [103]). This technique can identify the rodent neurons influenced by drug exposure as indexed by expression levels of immediate-early genes such as the fos/jun family under a variety of drug injection regimens. Using this molecular approach, the neuronal systems responsible for the state of AMPH withdrawal and the behavioral sensitization may be identified separately. In combination with this methodology, the visualization of genes and/or proteins responsible for monoamine availability (for example, DAT, VMAT-2, TH, MAO, and maybe SNARE proteins) and for the availability of other neurotransmitters including GABA and glutamate in animal models will help us understand the regulation of neuronal excitability relevant to aversive subjective symptoms of AMPH withdrawal in humans. Acknowledgments N. K. was supported, in part, by a Grant-in-Aid for Researchers, Hyogo College of Medicine. The authors thank anonymous reviewers for their very helpful comments on an earlier version of the manuscript.

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