Abstract
High doses of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine can elicit somatic signs resembling those associated with nicotine withdrawal in nicotine-naïve adult rats. Understanding this phenomenon, and its possible modulation by acute nicotine and age, could inform the use of mecamylamine as both an experimental tool and potential pharmacotherapy for tobacco dependence and other disorders. This study evaluated the ability of high-dose mecamylamine to elicit somatic signs in adolescent rats, and the potential for acute nicotine pretreatment to potentiate this effect as previously reported in adults. Single or repeated injections of mecamylamine (1.5 or 3.0 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents, but this effect was not influenced by 2 h pretreatment with acute nicotine (0.5 mg/kg, s.c.). In an initial evaluation of the effects of age in this model, mecamylamine (2.25 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents and adults. This effect was modestly enhanced following acute nicotine injections in adults but not in adolescents, even when a higher nicotine dose (1.0 rather than 0.5 mg/kg, s.c.) was used in adolescents to account for age differences in nicotine pharmacokinetics. These studies are the first to show that mecamylamine elicits somatic signs in nicotine-naïve adolescent rats, an effect that should be considered when designing and interpreting studies examining effects of high doses of mecamylamine in adolescents. Our findings also provide preliminary evidence that these signs may be differentially modulated by acute nicotine pretreatment in adolescents versus adults.
Highlights
The non-selective nicotinic acetylcholine receptor antagonist mecamylamine is commonly used in preclinical models
Sessions 1–5 Single or repeated injections of mecamylamine alone (1.5 or 3.0 mg/kg, s.c.) elicited somatic signs in adolescent rats, but this effect was not influenced by 2 h pretreatment with nicotine (0.5 mg/kg, s.c.; Figures 1A,B)
This study evaluated the ability of high-dose mecamylamine to elicit somatic signs in nicotine-naïve adolescent rats, and the potential for acute nicotine pretreatment to potentiate this effect as previously reported in adults
Summary
The non-selective nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine is commonly used in preclinical models. Mecamylamine can itself elicit somatic signs in nicotinenaïve rats that resemble those associated with nicotine withdrawal (Malin et al, 1994; Harrison et al, 2001; Wing and Shoaib, 2007; Guillem et al, 2008; Harris et al, 2013), as well as other behavioral effects including suppression of operant responding (Levin et al, 2000; Vann et al, 2006), Somatic signs in adolescent rats cognitive effects (Levin et al, 1987, 2000; Sanders et al, 2010), and aversion (Watkins et al, 2000; Guillem et al, 2008) These effects of mecamylamine alone presumably reflect antagonism of endogenous nAChRs, which are prominently expressed in numerous brain areas that mediate behavior including the ventral tegmental area, hippocampus, medial habenula, and interpeduncular nucleus (Wada et al, 1989; Gotti et al, 2006, 2009; Fowler et al, 2008). In addition to informing the use of mecamylamine as both an experimental tool and putative pharmacotherapy, studying the behavioral effects of mecamylamine alone could provide important basic scientific knowledge on the function of the cholinergic system
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