Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
Neuropsychopharmacology. 2011 Apr;36(5):993-1002. doi: 10.1038/npp.2010.237. Epub 2011 Jan 19.
Alcoholism is characterized by compulsive alcohol intake after a history of chronic consumption. A reduction in mesolimbic dopaminergic transmission observed during abstinence may contribute to the negative affective state that drives compulsive intake. Although previous in vivo recording studies in rodents have demonstrated profound decreases in the firing activity of ventral tegmental area (VTA) dopamine neurons after withdrawal from long-term ethanol exposure, the cellular mechanisms underlying this reduced activity are not well understood. Somatodendritic dopamine release within the VTA exerts powerful feedback inhibition of dopamine neuron activity via stimulation of D(2) autoreceptors and subsequent activation of G protein-gated inwardly rectifying K(+) (GIRK) channels. Here, by performing patch-clamp recordings from putative dopamine neurons in the VTA of mouse brain slices, we show that D(2) receptor/GIRK-mediated inhibition becomes more potent and exhibits less desensitization after withdrawal from repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 days). In contrast, GABA(B) receptor/GIRK-mediated inhibition and its desensitization are not affected. Chelating cytosolic Ca(2+) with BAPTA augments D(2) inhibition and suppresses its desensitization in control mice, while these effects of BAPTA are occluded in ethanol-treated mice. Furthermore, inositol 1,4,5-trisphosphate (IP(3))-induced intracellular Ca(2+) release and Ca(2+)/calmodulin-dependent protein kinase II are selectively involved in the desensitization of D(2), but not GABA(B), receptor signaling. Consistent with this, activation of metabotropic glutamate receptors that are coupled to IP(3) generation leads to cross-desensitization of D(2)/GIRK-mediated responses. We propose that enhancement of D(2) receptor-mediated autoinhibition via attenuation of a Ca(2+)-dependent desensitization mechanism may contribute to the hypodopaminergic state during ethanol withdrawal.
酒精成瘾的特征是在长期饮酒后出现强迫性饮酒。在戒断期间观察到的中脑边缘多巴胺传递减少可能导致驱动强迫性摄入的负面情感状态。尽管以前在啮齿动物的体内记录研究表明，从长期乙醇暴露中戒断后，腹侧被盖区（VTA）多巴胺神经元的放电活动会显著降低，但这种活性降低的细胞机制尚不清楚。VTA 内的树突状多巴胺释放通过刺激 D2 自身受体和随后激活 G 蛋白门控内向整流钾（GIRK）通道，对多巴胺神经元活动施加强大的反馈抑制。在这里，通过在小鼠脑切片的 VTA 中进行推测的多巴胺神经元的膜片钳记录，我们显示 D2 受体/GIRK 介导的抑制在从反复体内乙醇暴露（2g/kg，腹腔内，每天三次，持续 7 天）中戒断后变得更强，并且表现出较少的脱敏。相比之下，GABA（B）受体/GIRK 介导的抑制及其脱敏不受影响。用 BAPTA 螯合细胞质 Ca2+ 可增强 D2 抑制并抑制其在对照小鼠中的脱敏，而在乙醇处理的小鼠中，BAPTA 的这些作用被阻断。此外，三磷酸肌醇（IP3）诱导的细胞内 Ca2+释放和 Ca2+/钙调蛋白依赖性蛋白激酶 II 特异性参与 D2 受体信号转导的脱敏，但不参与 GABA（B）受体信号转导的脱敏。与此一致，与 IP3 生成偶联的代谢型谷氨酸受体的激活导致 D2/GIRK 介导的反应的交叉脱敏。我们提出，通过减弱依赖 Ca2+的脱敏机制，增强 D2 受体介导的自身抑制可能有助于乙醇戒断期间的低多巴胺状态。
