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 Î±6 subunit message is abundant in the VTA, but Î±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 Î±6Î²2*-nAChR expression on GABA neuronal boutons terminating on VTA DA neurons. Î±-Conotoxin (Î±-Ctx) MII labeling coupled with immunocytochemical staining localizes putative Î±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 GABAA receptors. These increases are abolished by Î±6*-nAChR-selective Î±-Ctx MII or Î±-Ctx PIA (1 nM) but not by Î±7 (10 nM methyllycaconitine) or Î±4* (1 Î¼M dihydro-Î²-erythroidine)-nAChR-selective antagonists. ACh also fails to increase mIPSC frequency in VTA DA neurons prepared from nAChR Î²2 knock-out mice. Moreover, ACh induces an Î±-Ctx PIA-sensitive elevation in intraterminal Ca2+ 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 Î±6Î²2*-nAChRs are located on presynaptic GABAergic boutons within the VTA and modulate GABA release onto DA neurons. These presynaptic Î±6Î²2*-nAChRs likely play important roles in nicotinic modulation of DA neuronal activity. Copyright Â© 2011 the authors.
Journal of Neuroscience
Digital Object Identifier (DOI)
Yang, Kechun; Buhlman, Lori; Khan, Ghous M.; Nichols, Robert A.; Jin, Guozhang; McIntosh, J. Michael; Whiteaker, Paul; Lukas, Ronald J.; and Wu, Jie, "Functional Nicotinic Acetylcholine Receptors Containing Î±6 Subunits Are On Gabaergic Neuronal Boutons Adherent To Ventral Tegmental Area Dopamine Neurons" (2011). Neurobiology. 223.