Psychopharmacology (2013) 225:291–302 DOI 10.1007/s00213-012-2814-x
ORIGINAL INVESTIGATION
Mecamylamine elicits withdrawal-like signs in rats following a single dose of nicotine Andrew C. Harris & Katherine E. Manbeck & Clare E. Schmidt & David Shelley
Received: 13 January 2012 / Accepted: 16 July 2012 / Published online: 7 August 2012 # Springer-Verlag 2012
Abstract Rationale The ability of nicotine to induce dependence (result in a withdrawal syndrome) is typically thought to require long-term, daily smoking. Emerging evidence suggests that symptoms of nicotine withdrawal may occur following only a few cigarettes. Whether acute exposure to nicotine can induce dependence in animals has not been well established. Objective The objective of this paper is to examine whether the nicotinic acetylcholine receptor antagonist mecamylamine elicits withdrawal-like signs in rats following acute nicotine exposure. Methods and Results Mecamylamine (3.0 mg/kg, s.c.) administered ≈2 h after a single dose of nicotine (0.5 mg/kg, s.c.) elicited increases in intracranial self-stimulation (ICSS) thresholds and somatic signs, two well-established effects of withdrawal from long-term (chronic) nicotine exposure. The magnitude of these effects remained constant across five daily test sessions. A lower dose of mecamylamine (1.5 mg/kg, s.c.) had little or no effect on ICSS thresholds or somatic signs following acute nicotine exposure, but precipitated robust increases in these measures during a chronic nicotine infusion. A. C. Harris (*) : K. E. Manbeck : C. E. Schmidt : D. Shelley Minneapolis Medical Research Foundation, 914 South 8th St. S-3 Labs, 860, Minneapolis, MN 55404, USA e-mail:
[email protected] A. C. Harris Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA K. E. Manbeck Department of Psychology, University of Minnesota, Minneapolis, MN, USA C. E. Schmidt Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
Finally, rats exhibited a small increase in ICSS thresholds over time following a single nicotine injection (0.5 mg/kg, s.c.), possibly reflecting a modest spontaneous withdrawal-like effect. Conclusions Mecamylamine elicited withdrawal-like signs in rats following a single dose of nicotine. The different effects of mecamylamine 1.5 mg/kg following acute versus chronic nicotine exposure supports the notion that these models simulate the early and more advanced stages of nicotine dependence, respectively. While further optimization and validation of these models is necessary, they may provide a novel approach for studying the earliest stages of nicotine dependence. Keywords Nicotine . Withdrawal . Intracranial selfstimulation . Somatic signs . Acute dependence . Mecamylamine
Introduction The ability of nicotine to induce dependence, defined by the emergence of a withdrawal syndrome following cessation of nicotine exposure, may contribute to tobacco addiction (Baker et al. 2004; Hughes 2007; Markou 2008). Although development of nicotine dependence is typically thought to require long-term, daily smoking, some symptoms of nicotine withdrawal (e.g., depression, anxiety) have been reported in adolescents following only a few cigarettes (Difranza 2010; DiFranza et al. 2000; DiFranza et al. 2007; DiFranza and Wellman 2005; O’Loughlin et al. 2003). In addition, development of these early withdrawal symptoms or other measures of “diminished autonomy” over tobacco (e.g., craving, tolerance) predicted the progression to daily smoking and vulnerability to relapse (Difranza 2010; DiFranza et al. 2007; DiFranza et al. 2002; Doubeni et al. 2010). While these findings have been controversial (Dar
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and Frenk 2010; Hughes and Shiffman 2008), they raise the possibility that nicotine dependence develops rapidly and contributes to the early development of tobacco addiction. Animal models are commonly used to study nicotine dependence. Typically, animals are exposed to a continuous nicotine infusion or daily nicotine injections for at least 1 week prior to assessment of withdrawal, which can be elicited via cessation of nicotine exposure (spontaneous withdrawal) or administration of a nicotinic acetylcholine receptor (nAChR) antagonist such as mecamylamine (precipitated withdrawal) (e.g., Cheeta et al. 2001; Corrigall et al. 1989; Epping-Jordan et al. 1998; Harris et al. 2010; Malin and Goyarzu 2009). These “chronic dependence” models are very useful for examining factors associated with the expression of withdrawal in dependent subjects. However, they may be less ideal for isolating the early processes underlying the development of dependence in nicotine-naïve subjects. The study of “acute dependence”, in which withdrawal signs are measured after just a single dose of a drug and often increase in magnitude across repeated exposures, has been useful for characterizing the early stages of dependence on several addictive drugs including opiates, alcohol, and benzodiazepines (Adams and Holtzman 1990; Bronson 1994; Harris and Gewirtz 2004; 2005; Liu and Schulteis 2004; Schulteis and Liu 2006). While a single dose or limited exposure to nicotine can induce certain addiction-related phenomena in animals (e.g., tolerance, locomotor sensitization) (DiFranza and Wellman 2007; James et al. 1994; Rosecrans et al. 1995), only a few studies have examined whether short-term nicotine exposure produces dependence. Spontaneous or precipitated withdrawal-induced suppression of operant responding was reported following three daily nicotine injections (Morrison 1974) or 4 days of a continuous nicotine infusion (Vann et al. 2006a), respectively. However, Vann et al. (2006a) did not observe precipitated withdrawal following a 3-day nicotine infusion. In addition, spontaneous withdrawal-induced increases in acoustic startle responding (a putative measure of anxiety-like behavior) were not observed following a single nicotine injection (Engelmann et al. 2009). Therefore, while some preclinical studies suggest that dependence may develop following relatively limited nicotine exposure (i.e.,
