ORIGINAL INVESTIGATION Differential effects of nicotinic antagonists perfused into the nucleus accumbens or the ventral tegmental area on cocaine-induced dopamine release in the nucleus accumbens of mice Lara Zanetti & Marina R. Picciotto & Michele Zoli Received: 9 May 2006 / Accepted: 21 September 2006 / Published online: 24 October 2006 # Springer-Verlag 2006 Abstract Rationale The mesolimbic dopamine (DA) system is considered a principal site for nicotine–cocaine interactions. Objectives and methods The aim of this paper is to study the effects of local perfusions (through the microdialysis cannula) of nicotinic acetylcholine receptor (nAChR) antagonists in the ventral tegmental area (VTA, where mesolimbic DA cell bodies are located) or nucleus accumbens (nAc, where mesolimbic DA nerve terminals project) on cocaine-elicited increase in DA levels in the nAc of mice using intracerebral microdialysis. Results Intra-nAc perfusion of mecamylamine (a nonselec- tive central nicotinic antagonist) or coperfusion of methyl- lycaconitine (MLA, 10 nM) and dihydro-β-erythroidine (DHβE, 10–100 μM) decreased cocaine-elicited increase in DA perfusate levels. In contrast, intra-nAc perfusion of MLA alone (a relatively selective antagonist of α7 subunit- containing nAChRs) increased, while DHβE (a relatively selective antagonist of heteromeric nAChR subtypes) did not alter, cocaine-elicited increase in DA perfusate levels. Intra-VTA perfusion of MLA (100 nM) or DHβE (100 μM) significantly increased the cocaine-elicited increase of DA levels in the nAc or VTA, whereas DHβE and MLA coperfusion or mecamylamine perfusion had no significant effect. Conclusions These results show that intra-nAc and intra- VTA perfusion of nAChR antagonists differentially affect cocaine-elicited increase in DA levels in a region and subtype-specific manner. This suggests that multiple cho- linergic/nicotinic pathways influence the effects of cocaine on mesolimbic DA neurons in complex, and sometimes opposing, patterns. Keywords Cocaine . Dopamine . Mecamylamine . Methyllycaconitine . Dihydro-β-erythroidine . Double-probe microdialysis . Mice Introduction Both human and animal studies suggest that there is an interaction between effects of nicotine and cocaine. Ciga- rette smoking and cocaine addiction are positively corre- lated (Budney et al. 1993), and cigarette smoking during adolescence can predispose an individual to other forms of drug abuse (Lindsay and Rainey 1997). The effects of cigarette smoking on cocaine abuse are thought to be a result of nicotine exposure. Accordingly, nicotinic agonists and antagonists can modulate the effects of cocaine in human subjects and in animal models. In smokers, an acute dose of nicotine can trigger cocaine craving, whereas a nicotinic antagonist can block cue-induced craving for cocaine (Reid et al. 1998, 1999). In rodents, nicotine treatment increases self-administration of cocaine (Horger et al. 1992) and facilitates relapse to cocaine seeking (Bechtholt and Mark 2002). On the other hand, adminis- tration of mecamylamine [a general nicotinic antagonist that is not highly selective for individual nicotinic acetyl- choline receptor (nAChR) subtypes] or knockout of Psychopharmacology (2007) 190:189–199 DOI 10.1007/s00213-006-0598-6 L. Zanetti : M. Zoli (*) Department of Biomedical Sciences, Section of Physiology, University of Modena and Reggio Emilia, via Campi 287, 41100 Modena, Italy e-mail: mzoli@unimo.it L. Zanetti : M. R. Picciotto Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA