Functional nicotinic acetylcholine receptors containing ?6 subunits are on GABAergic neuronal boutons adherent to ventral tegmental area dopamine neurons.

ABSTRACT: Diverse nicotinic acetylcholine receptor (nAChR) subtypes containing different subunit combinations can be placed on nerve terminals or soma/dendrites in the ventral tegmental area (VTA). nAChR ?6 subunit message is abundant in the VTA, but ?6*-nAChR cellular localization, function, pharmacology, and roles in cholinergic modulation of dopaminergic (DA) neurons within the VTA are not well understood. Here, we report evidence for ?6?2*-nAChR expression on GABA neuronal boutons terminating on VTA DA neurons. ?-Conotoxin (?-Ctx) MII labeling coupled with immunocytochemical staining localizes putative ?6*-nAChRs to presynaptic GABAergic boutons on acutely dissociated, rat VTA DA neurons. Functionally, acetylcholine (ACh) induces increases in the frequency of bicuculline-, picrotoxin-, and 4-aminopyridine-sensitive miniature IPSCs (mIPSCs) mediated by GABA(A) receptors. These increases are abolished by ?6*-nAChR-selective ?-Ctx MII or ?-Ctx PIA (1 nm) but not by ?7 (10 nm methyllycaconitine) or ?4* (1 ?m dihydro-?-erythroidine)-nAChR-selective antagonists. ACh also fails to increase mIPSC frequency in VTA DA neurons prepared from nAChR ?2 knock-out mice. Moreover, ACh induces an ?-Ctx PIA-sensitive elevation in intraterminal Ca(2+) in synaptosomes prepared from the rat VTA. Subchronic exposure to 500 nm nicotine reduces ACh-induced GABA release onto the VTA DA neurons, as does 10 d of systemic nicotine exposure. Collectively, these results indicate that ?6?2*-nAChRs are located on presynaptic GABAergic boutons within the VTA and modulate GABA release onto DA neurons. These presynaptic ?6?2*-nAChRs likely play important roles in nicotinic modulation of DA neuronal activity.

SUBMITTER: Yang K 

PROVIDER: S-EPMC3081713 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature