Expression of sensitized ß2 nAChR subunits in VTA neurons enhances intravenous nicotine self-administration in male rats.

ABSTRACT

Ventral tegmental area (VTA) nicotinic acetylcholine receptors (nAChRs) are important for nicotine reinforcement. To determine whether and to what extent these receptors are sufficient for nicotine reinforcement, we expressed ß2Leu9'Ser (i.e. sensitized) nAChR subunits in the VTA of adult male rats and assessed the nicotine dose-response relationship in intravenous self-administration (SA). ß2Leu9'Ser rats self-administered nicotine doses 50-100 fold lower than the lowest doses that control rats would respond for. Expression of WT ß2 subunits confirmed that this enhanced sensitivity to nicotine was due to the Leu9'Ser mutation in ß2. Higher unit doses were associated with strong escalation in ß2Leu9'Ser rats over 17 fixed ratio sessions. Escalation was minimal or absent in control rats at the same unit doses. In progressive ratio SA, ß2Leu9'Ser rats exhibited higher breakpoints than control rats when the nicotine unit dose was 1.5 µg/kg/inf or higher. In intermittent access SA, ß2Leu9'Ser rats exhibited response patterns very similar to control rats. By adding nicotine dose-response data, progressive ratio assays, and intermittent access results that rule out stereotypy, these data significantly extend our previous finding that nicotine activation of the mesolimbic dopamine pathway is sufficient for nicotine reinforcement.