Yorgason J T, Rose J H, McIntosh J M, Ferris M J, Jones S R
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157, United States.
George E. Wahlen Veterans Affairs Medical Center and Departments of Psychiatry and Biology, University of Utah, Salt Lake City, UT 84108, United States.
Neuroscience. 2015 Jan 22;284:854-864. doi: 10.1016/j.neuroscience.2014.10.052. Epub 2014 Nov 4.
The mesolimbic dopamine system, originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc), has been heavily implicated in the reinforcing effects of ethanol. Recent slice voltammetry studies have shown that ethanol inhibits dopamine release selectively during high-frequency activity that elicits phasic dopamine release shown to be important for learning and reinforcement. Presently, we examined ethanol inhibition of electrically evoked NAc dopamine in two mouse strains with divergent dopamine responses to ethanol, C57BL/6 (C57) and DBA/2J (DBA) mice. Previous electrophysiology and microdialysis studies have demonstrated greater ethanol-induced VTA dopaminergic firing and NAc dopamine elevations in DBA compared to C57 mice. Additionally, DBA mice have greater ethanol responses in dopamine-related behaviors, including hyperlocomotion and conditioned place preference. Currently, we demonstrate greater sensitivity of ethanol inhibition of NAc dopamine signaling in C57 compared to DBA mice. The reduced sensitivity to ethanol inhibition in DBA mice may contribute to the overall greater ethanol-induced dopamine signaling and related behaviors observed in this strain. NAc cholinergic activity is known to potently modulate terminal dopamine release. Additionally, ethanol is known to interact with multiple aspects of nicotinic acetylcholine receptor activity. Therefore, we examined ethanol-mediated inhibition of dopamine release at two ethanol concentrations (80 and 160 mM) during bath application of the non-selective nicotinic receptor antagonist mecamylamine, as well as compounds selective for the β2-(dihydro-β-erythroidine hydrobromide; DhβE) and α6-(α-conotoxin MII [H9A; L15A]) subunit-containing receptors. Mecamylamine and DhβE decreased dopamine release and reduced ethanol's inhibitory effects on dopamine in both DBA and C57 mice. Further, α-conotoxin also reduced the dopamine release and the dopamine-inhibiting effects of ethanol at the 80 mM, but not 160 mM, concentration. These data suggest that ethanol is acting in part through nicotinic acetylcholine receptors, or downstream effectors, to reduce dopamine release during high-frequency activity.
中脑边缘多巴胺系统起源于腹侧被盖区（VTA），并投射到伏隔核（NAc），该系统与乙醇的强化作用密切相关。最近的脑片伏安法研究表明，乙醇在引发时相性多巴胺释放的高频活动期间选择性抑制多巴胺释放，而时相性多巴胺释放对学习和强化很重要。目前，我们研究了乙醇对两种对乙醇有不同多巴胺反应的小鼠品系——C57BL/6（C57）和DBA/2J（DBA）小鼠中电诱发的NAc多巴胺的抑制作用。先前的电生理学和微透析研究表明，与C57小鼠相比，DBA小鼠中乙醇诱导的VTA多巴胺能神经元放电和NAc多巴胺升高更为明显。此外，DBA小鼠在与多巴胺相关的行为中，包括运动亢进和条件性位置偏爱，对乙醇的反应更强。目前，我们证明与DBA小鼠相比，C57小鼠中乙醇对NAc多巴胺信号传导的抑制作用更敏感。DBA小鼠对乙醇抑制的敏感性降低可能导致该品系中总体上更大的乙醇诱导的多巴胺信号传导及相关行为。已知NAc胆碱能活动可有效调节终末多巴胺释放。此外，已知乙醇与烟碱型乙酰胆碱受体活性的多个方面相互作用。因此，我们在浴加非选择性烟碱受体拮抗剂美加明以及对含β2-（氢溴酸二氢-β-刺桐啶；DhβE）和α6-（α-芋螺毒素MII [H9A；L15A]）亚基的受体具有选择性的化合物期间，研究了两种乙醇浓度（80和160 mM）下乙醇介导的多巴胺释放抑制作用。美加明和DhβE均降低了DBA和C57小鼠中的多巴胺释放，并减弱了乙醇对多巴胺的抑制作用。此外，α-芋螺毒素在80 mM而非160 mM浓度下也降低了多巴胺释放以及乙醇对多巴胺的抑制作用。这些数据表明，乙醇部分通过烟碱型乙酰胆碱受体或下游效应器发挥作用，以减少高频活动期间的多巴胺释放。
