Nicotine receptor inactivation decreases sensitivity to cocaine

The reinforcing properties of nicotine and psyhomotor stimulants are though t to be mediated through the mesolimbic dopamine (DA) system. This study in vestigates the role of high affinity nicotinic acetylcholine receptors (nAC hRs) in cocaine place preference and examines some neurochemical changes in the mesolimbic DA system that might account for the interaction between ni cotine 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 antago nist mecamylamine (1.0 mg/kg) disrupted place preference to 5 mg/kg cocaine . In addition, mice lacking the high affinity nAChR containing the beta2 su bunit showed decreased place preference to 5 mg/kg cocaine, although higher doses of cocaine could condition a place preference in these knock out ani mals. 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). D A turnover was monitored in several brain regions using tissue levels of DA and ifs 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 re duced in mutant mice as compared to their wild type siblings, implying that downstream actions of cocaine were also affected by inactivation of the hi gh affinity nAChR. These data indicate that activation of the high affinity nAChR may contribute to cocaine reinforcement. (C) 2 001 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.