Department of Psychology and Neuroscience, Brigham Young University, Provo, UT, USA.
Department of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
Addict Biol. 2018 Sep;23(5):1079-1093. doi: 10.1111/adb.12559. Epub 2017 Sep 13.
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 α6 subunit-containing nAChRs (α6*-nAChRs) in acute ethanol effects on ventral tegmental area (VTA) GABA and DA neurons. α6*-nAChRs were visualized on GABA terminals on VTA GABA neurons, and α6*-nAChR transcripts were expressed in most DA neurons, but only a minority of VTA GABA neurons from GAD67 GFP mice. Low concentrations of ethanol (1-10 mM) enhanced GABA receptor (GABA R)-mediated spontaneous and evoked inhibition with blockade by selective α6*-nAChR antagonist α-conotoxins (α-Ctxs) and lowered sensitivity in α6 knock-out (KO) mice. Ethanol suppression of VTA GABA neuron firing rate in wild-type mice in vivo was significantly reduced in α6 KO mice. Ethanol (5-100 mM) had no effect on optically evoked GABA R-mediated inhibition of DA neurons, and ethanol enhancement of VTA DA neuron firing rate at high concentrations was not affected by α-Ctxs. Ethanol conditioned place preference was reduced in α6 KO mice compared with wild-type controls. Taken together, these studies indicate that relatively low concentrations of ethanol act through α6*-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.
多巴胺 (DA) 神经元的兴奋性受抑制性 GABA 能突触传递的调节，并受烟碱型乙酰胆碱受体 (nAChRs) 调节。本研究旨在评估含有 α6 亚基的 nAChRs（α6*-nAChRs）在急性乙醇对腹侧被盖区 (VTA) GABA 和 DA 神经元的影响中的作用。在 VTA GABA 神经元的 GABA 末梢上观察到 α6*-nAChRs，并且在 GAD67 GFP 小鼠的大多数 DA 神经元中表达 α6*-nAChR 转录本，但只有少数 VTA GABA 神经元表达。低浓度乙醇 (1-10 mM) 增强了 GABA 受体 (GABA R) 介导的自发性和诱发性抑制，这种抑制可被选择性 α6*-nAChR 拮抗剂 α-芋螺毒素 (α-Ctxs) 阻断，并降低了 α6 敲除 (KO) 小鼠的敏感性。在体内，野生型小鼠 VTA GABA 神经元放电率的乙醇抑制在 α6 KO 小鼠中显著降低。乙醇 (5-100 mM) 对光诱发的 GABA R 介导的 DA 神经元抑制没有影响，而高浓度乙醇增强 VTA DA 神经元放电率不受 α-Ctxs 的影响。与野生型对照相比，α6 KO 小鼠的乙醇条件性位置偏好降低。综上所述，这些研究表明，相对低浓度的乙醇通过 GABA 末梢上的 α6*-nAChRs 作用，增强 GABA 对 VTA GABA 神经元的释放，进而降低 GABA 神经元的放电率，这可能导致 VTA DA 神经元去抑制，提示酒精和尼古丁共滥用的一种可能作用机制。
