The reinforcing properties of nicotine and psychomotor stimulants are thought to be mediated through the mesolimbic dopamine (DA) system. This study investigates the role of high affinity nicotinic acetylcholine receptors (nAChRs) in cocaine place preference and examines some neurochemical changes in the mesolimbic DA system that might account for the interaction between nicotine and cocaine. 5 mg/kg is the lowest dose of cocaine able to condition a place preference in C57Bl/6 mice. Co-treatment with the nicotinic antagonist mecamylamine (1.0 mg/kg) disrupted place preference to 5 mg/kg cocaine. In addition, mice lacking the high affinity nAChR containing the beta2 subunit showed decreased place preference to 5 mg/kg cocaine, although higher doses of cocaine could condition a place preference in these knock out animals. In contrast, co-administration of a low dose of nicotine (0.2 mg/kg) potentiated place preference to a subthreshold dose of cocaine (3 mg/kg). DA turnover was monitored in several brain regions using tissue levels of DA and its primary metabolite DOPAC as an indication of DA release. Wild type mice showed decreased DA turnover following treatment with 5 mg/kg cocaine; whereas, this response was not seen in mice lacking the beta2 subunit of the nAChR. Induction of chronic fos-related antigens by cocaine was also reduced in mutant mice as compared to their wild type siblings, implying that downstream actions of cocaine were also affected by inactivation of the high affinity nAChR. These data indicate that activation of the high affinity nAChR may contribute to cocaine reinforcement.