Psychopharmacology (2005) 178: 183–192 DOI 10.1007/s00213-004-2007-3 ORIGINAL INVESTIGATION Sheri D. Grabus . Billy R. Martin . Angela M. Batman . Rachel F. Tyndale . Edward Sellers . M. Imad Damaj Nicotine physical dependence and tolerance in the mouse following chronic oral administration Received: 13 January 2004 / Accepted: 28 July 2004 / Published online: 10 September 2004 # Springer-Verlag 2004 Abstract Rationale: Although nicotine dependence and tolerance develop in rats, few studies have examined these processes in the mouse. Establishing such mouse models would eventually allow for an examination of the role of specific nicotinic receptor subtypes in mediating these processes (i.e. through the use of receptor knockouts). Objectives: The goals of the present study were to establish mouse models of nicotine dependence and tolerance. Methods: Mice were chronically exposed to nicotine (0–200 μg/ml) in their drinking solution and assayed for plasma nicotine and cotinine levels, with- drawal signs following nicotine cessation (spontaneous withdrawal) or nicotinic antagonist administration (pre- cipitated withdrawal), or nicotine tolerance. Dependence assays included somatic sign observations (paw tremors, backing and head shakes), tail-flick, plantar stimulation, elevated plus-maze and spontaneous activity. Tolerance was assayed using tail-flick, hot-plate and body temper- ature tests. Results: Plasma nicotine and cotinine levels were elevated during oral nicotine exposure (15.85 ng/ml and 538.00 ng/ml, respectively) and quickly declined following nicotine cessation (<1 ng/ml and <2 ng/ml, respectively), providing evidence that the oral route was pharmacologically relevant. Nicotine withdrawal in- creased numbers of somatic signs (spontaneous and mecamylamine-precipitated withdrawal) and/or hyperal- gesia (spontaneous withdrawal only). Chronic nicotine exposure also produced tolerance, as indicated by reduced responsivity to acute nicotine in assays of analgesia and hypothermia. Conclusions: These results indicate that chronic oral nicotine produces dependence and tolerance in the mouse. Further, nicotine dependence may be mediated by multiple nicotinic receptor subtypes, since specific nicotinic receptor antagonists failed to precipitate withdrawal. Keywords Nicotine . Withdrawal . Dependence . Tolerance . Mice Introduction Both dependence and tolerance develop as a result of chronic nicotine intake, so continued nicotine use could be due to one or both of these factors. The development of animal models of nicotine dependence and tolerance has allowed for an examination of these processes. For example, compared to saline-infused controls, rats chroni- cally exposed to nicotine demonstrated increased numbers of abstinence signs following nicotine cessation (sponta- neous withdrawal) (Malin et al. 1994, 1992) or adminis- tration of the nicotinic antagonists (precipitated withdraw- al) mecamylamine (Hildebrand et al. 1999), hexametho- nium (Malin et al. 1997) and dihydro-β-erythroidine (DHβE) (Malin et al. 1997, 1998). Similar effects have been found in nicotine-dependent mice, with these subjects demonstrating increased withdrawal signs (Isola et al. 1999; Damaj et al. 2003) and hyperalgesia (Damaj et al. 2003) following nicotine cessation and mecamylamine injection. In addition to producing dependence, chronic nicotine also generates tolerance in rodents. Specifically, mice or rats chronically exposed to nicotine demonstrated reduced responsivity to acute nicotine in assays of analgesia (Damaj and Martin 1996; McCallum et al. 1999), hypo- thermia (Robinson et al. 1996), convulsion (Okamoto et al. 1992), anxiolysis (Szyndler et al. 2001), locomotion and heart rate (Robinson et al. 1996). Although nicotine dependence and tolerance have been studied in rats, few studies have examined these processes in mice. There are few articles on rodent dependence models, and the majority of these studies have utilized rats S. D. Grabus (*) . B. R. Martin . A. M. Batman . M. I. Damaj Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Campus, PO Box 980613 Richmond, VA 23298-0613, USA e-mail: sdgrabus@vcu.edu Tel.: +1-804-8282065 Fax: +1-804-8282117 R. F. Tyndale . E. Sellers Department of Pharmacology, CAMH, University of Toronto, Toronto, ON, Canada, M5S 1A8