Î±6 Subunit-Containing Nicotinic Receptors Mediate Low-Dose Ethanol Effects On Ventral Tegmental Area Neurons And Ethanol Reward
Dopamine (DA) neuron excitability is regulated by inhibitory GABAergic synaptic transmission and modulated by nicotinic acetylcholine receptors (nAChRs). The aim of this study was to evaluate the role of Î±6 subunit-containing nAChRs (Î±6*-nAChRs) in acute ethanol effects on ventral tegmental area (VTA) GABA and DA neurons. Î±6*-nAChRs were visualized on GABA terminals on VTA GABA neurons, and Î±6*-nAChR transcripts were expressed in most DA neurons, but only a minority of VTA GABA neurons from GAD67 GFP mice. Low concentrations of ethanol (1â€“10Â mM) enhanced GABA A receptor (GABA A R)-mediated spontaneous and evoked inhibition with blockade by selective Î±6*-nAChR antagonist Î±-conotoxins (Î±-Ctxs) and lowered sensitivity in Î±6 knock-out (KO) mice. Ethanol suppression of VTA GABA neuron firing rate in wild-type mice in vivo was significantly reduced in Î±6 KO mice. Ethanol (5â€“100Â mM) had no effect on optically evoked GABA A R-mediated inhibition of DA neurons, and ethanol enhancement of VTA DA neuron firing rate at high concentrations was not affected by Î±-Ctxs. Ethanol conditioned place preference was reduced in Î±6 KO mice compared with wild-type controls. Taken together, these studies indicate that relatively low concentrations of ethanol act through Î±6*-nAChRs on GABA terminals to enhance GABA release onto VTA GABA neurons, in turn to reduce GABA neuron firing, which may lead to VTA DA neuron disinhibition, suggesting a possible mechanism of action of alcohol and nicotine co-abuse.
Digital Object Identifier (DOI)
Steffensen, Scott C.; Shin, Samuel I.; Nelson, Ashley C.; Pistorius, Stephanie S.; Williams, Stephanie B.; Woodward, Taylor J.; Park, Hyun Jung; Friend, Lindsey; Gao, Ming; Gao, Fenfei; Taylor, Devin H.; Olive, M. Foster; Edwards, Jeffrey G.; Sudweeks, Sterling N.; Buhlman, Lori M.; McIntosh, J. Michael; and Wu, Jie, "Î±6 Subunit-Containing Nicotinic Receptors Mediate Low-Dose Ethanol Effects On Ventral Tegmental Area Neurons And Ethanol Reward" (2018). Neurobiology. 437.