Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area.

ABSTRACT: Nicotine activation of nicotinic acetylcholine receptors (nAChRs) within the dopaminergic (DAergic) neuron-rich ventral tegmental area (VTA) is necessary and sufficient for nicotine reinforcement. In this study, we show that rewarding doses of nicotine activated VTA DAergic neurons in a region-selective manner, preferentially activating neurons in the posterior VTA (pVTA) but not in the anterior VTA (aVTA) or in the tail VTA (tVTA). Nicotine (1??M) directly activated pVTA DAergic neurons in adult mouse midbrain slices, but had little effect on DAergic neurons within the aVTA. Quantification of nAChR subunit gene expression revealed that pVTA DAergic neurons expressed higher levels of ?4, ?6, and ?3 transcripts than did aVTA DAergic neurons. Activation of nAChRs containing the ?4 subunit (?4(*) nAChRs) was necessary and sufficient for activation of pVTA DAergic neurons: nicotine failed to activate pVTA DAergic neurons in ?4 knockout animals; in contrast, pVTA ?4(*) nAChRs were selectively activated by nicotine in mutant mice expressing agonist-hypersensitive ?4(*) nAChRs (Leu9'Ala mice). In addition, whole-cell currents induced by nicotine in DAergic neurons were mediated by ?4(*) nAChRs and were significantly larger in pVTA neurons than in aVTA neurons. Infusion of an ?6(*) nAChR antagonist into the VTA blocked activation of pVTA DAergic neurons in WT mice and in Leu9'Ala mice at nicotine doses, which only activate the mutant receptor indicating that ?4 and ?6 subunits coassemble to form functional receptors in these neurons. Thus, nicotine selectively activates DAergic neurons within the pVTA through ?4?6(*) nAChRs. These receptors represent novel targets for smoking-cessation therapies.

SUBMITTER: Zhao-Shea R 

PROVIDER: S-EPMC3077271 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature