Intracellular Study of Ethanol Effects on Brain Neurons

腹侧被盖区(VTA)中的多巴胺(DA)能神经元为核内的DA神经支配提供神经 伏隔核和前额叶皮质；这种中脑边缘多巴胺通路对大脑的奖赏特性很重要 乙醇。乙醇直接兴奋急性分离的DA-VTA神经元 ING细胞。兴奋多巴胺VTA神经元与动作电位降低有关 后超极化(AHP)表明这是由于钾(K)电流的减少 为AHP做出贡献。乙醇兴奋可被奎尼丁完全阻断，但不能被另一个钾通道阻断 拦截者。在全细胞电压钳实验中，乙醇降低了持续外向电流。这个 这个项目的总体目标是了解乙醇的细胞和分子机制 兴奋腹侧被盖区(VTA)的多巴胺能神经元，这是中脑边缘的起源细胞 多巴胺“奖赏”途径。我们研究的目标是了解 急性乙醇的奖赏效应及慢性过程中DA-VTA神经元反应的变化 饮酒会导致对酒精的渴望和上瘾。我们已将KCNQ确定为一个主要目标 对于乙醇对DA VTA神经元的作用，但它不是唯一的钾通道是靶点。功成名就 延伸期，我们将检验以下四个假设：1)DA VTA神经元的KCNQ通道是 对乙醇的抑制敏感。2)另一种快速激活、延迟整流钾通道也是 对乙醇敏感，并在维持放电频率方面发挥作用。3)DA VTA神经元的兴奋性为 被乙醇还原，这种影响与乙醇对放电频率的影响是分开的。4)乙醇- 兴奋性的诱导性降低是由酒精对产生 多巴胺VTA神经元的自发活动。一旦这些假设得到检验，这些技术和 已经产生的发现可以以多种方式应用，包括关联基因 这些膜通道与饮酒表型的同一性的差异，并确定 长期酒精暴露会导致这些离子通道及其对酒精的反应发生特定的变化。这个 这些研究的结果可能对理解乙醇对人的影响的差异具有重要意义。 与酒精中毒有关的大脑奖赏/强化通路。

Dopaminergic (DA) neurons in the ventral tegmental area (VTA) provide the DA innervation of the nucleus accumbens and prefrontal cortex; this mesolimbic DA pathway is important for the rewarding properties of ethanol. Ethanol directly excites acutely dissociated DA VTA neurons in the absence of input from surround- ing cells. Ehanol excitation of DA VTA neurons is associated with a reduction in the action potential afterhyperpolarization (AHP) suggesting that it is due to a decrease in a potassium (K) current which contributes to the AHP. Ethanol excitation is completely blocked by quinidine, but not by the other K channel blockers. In whole cell voltage clamp experiments, ethanol reduced the sustained outward current. The overall objective of this project is to understand the cellular and molecular mechanism by which ethanol excites dopaminergic (DA) neurons of the ventral tegmental area (VTA), the cells of origin of the mesolimbic dopamine "reward" pathway. The goal of our studies is to understand the physiological basis of the rewarding effects of acute ethanol and how changes in the response of DA VTA neurons during chronic alcohol consumption lead to alcohol craving and addiction. We have identified KCNQ as one primary target for ethanol action of DA VTA neurons, but it is not the only potassium channel which is a target. In the Merit Extension period, we will test the following four Hypotheses: 1) The KCNQ channels of DA VTA neurons are sensitive to inhibition by ethanol. 2) Another fast-activating, delayed rectifier potassium channel also is sensitive to ethanol and plays a role in maintaining firing frequency. 3) Excitability of DA VTA neurons is reduced by ethanol, and this effect is separate from the effect of ethanol on firing frequency. 4) Ethanol- induced reduction in excitability is mediated by an effect of alcohol on the mechanism of the generation of spontaneous activity in DA VTA neurons. Once these hypotheses have been tested, the techniques and findings that have been generated can be applied in a number of ways, including correlating genetic differences in the identity of these membrane channels with drinking phenotypes, and determining whether chronic alcohol exposure results in specific changes in these ion channels and their response to alcohol. The results of these studies could have major implications for understanding differences in ethanol effects on the reward/reinforcement pathways of the brain related to alcoholism.