MECHANISMS OF ADDICTION PATHOGENESIS

ARC的这一组成部分的目的是调查 GABA能神经传递，包括神经类固醇调节，在 大鼠酒精自我给药的启动和维持。那里 越来越多的行为学证据表明，中间边缘GABA系统 参与自愿的酒精自我给药。然而，有一个 我们对大脑中的分子机制的认识存在显著差距 酒精自我管理和偏好是基础。因为我们有 先前发现的GABAA受体敏感性改变的证据 以及在长期饮酒后皮质中的表达 建议研究中脑边缘的GABA能机制 长时间自我注射乙醇后的大脑区域。这些 研究将描绘GABAA的作用、受体功能和基因 乙醇自身给药在核内调控中的表达 伏隔核、腹侧被盖区、杏仁核和前额叶皮质。 我们还建议阐明神经类固醇调节剂在 乙醇自给药。我们计划确定是否启动和/或 维持乙醇自我给药改变内源性神经类固醇 合成或代谢，如果直接给神经类固醇给药 侧脑室或中脑边缘部位改变乙醇自身 行政管理。此前的研究表明，在 大鼠乙醇自我给药可能与性别有关 神经类固醇水平的差异。我们还发现了差异 大鼠大脑皮质GABAA受体α1亚单位表达的影响 雌鼠对雄鼠。我们建议确定性别是否会调节 GABAA受体功能、表达或神经类固醇代谢 GABA能中脑边缘环路在中枢神经系统启动或维持中的作用 自愿使用乙醇。最后，变化的影响 乙醇自身给药后GABAA受体表达的测定 使用载体介导的基因传递。 该组件旨在测试乙醇的总体假设 GABAA受体功能差异对自我给药的影响 和/或伏核、杏仁核、腹侧核的神经类固醇水平 被盖区和前额叶皮质。我们预测乙醇本身 给药将改变GABAA受体敏感性和神经类固醇 大脑中脑边缘环路的水平。这些更改将在 转向，规范乙醇自我管理，并为 酒精成瘾的发展。我们预测与性别有关的 这些系统的差异将与神经类固醇调节相关 伽玛受体。利用载体介导的基因转移，我们预计 能够操纵乙醇自我给药行为，显示出希望 寻找治疗酒精中毒的新方法。这些研究将使 对我们理解病因学和 酒精中毒的发病机制。

The purpose of this component of the ARC is to investigate the role of GABAergic neurotransmission, including neurosteroid modulation, in the initiation and maintenance of ethanol self-administration in rats. There is increasing behavioral evidence that mesolimbic GABA systems are involved in voluntary ethanol self-administration. However, there is a significant gap in our knowledge of the molecular mechanisms in brain that underlie alcohol self-administration and preference. Since we have previously found evidence for alterations in GABAa receptor sensitivity and expression in cortex following prolonged ethanol consumption, we propose to investigate the GABAergic mechanisms involved in mesolimbic brain regions following prolonged ethanol self-administration. These studies will delineate the role of GABAa, receptor function and gene expression in the control of ethanol self-administration in the nucleus accumbens, ventral tegmental area, amygdala and prefrontal cortex. We also propose to elucidate the role of neurosteroid modulators in ethanol self-administration. We plan to determine if the initiation and/or maintenance of ethanol self-administration alters endogenous neurosteroid synthesis or metabolism and if direct neurosteriod administration to the lateral ventricle, or mesolimbic brain sites alters ethanol self- administration. Previous studies have demonstrated gender differences in ethanol self-administration in the rat that could be related to gender differences in neurosteroid levels. We have also found differential effects on cerebral cortical GABAa receptor alpha1 subunit expression in female versus male rats. We propose to determine whether gender modulate GABAa receptor function, expression or neurosteriod metabolism in the GABAergic mesolimbic circuitry during initiation or maintenance of voluntary ethanol consumption. Finally, the effects of alterations in GABAa receptor expression on ethanol self-administration will be measured using vector-mediated gene delivery. This component is designed to test the overall hypothesis that ethanol self-administration is influence by differences in GABAa receptor function and/or neurosteroid levels in the nuclear accumbens, amygdala, ventral tegmental area and prefrontal cortex. We predict that ethanol self- administration will alter GABAa receptor sensitivity and neurosteroid levels in the mesolimbic circuitry of brain. These alterations will, in turn, regulate ethanol self-administration and contribute to the development of ethanol addiction. We predict that gender related differences in these systems will correlate with neurosteroid modulation of GAMAa receptors. Using vector-mediated gene transfer, we expect to be able to manipulate ethanol self-administration behavior, showing promise for new therapeutic approaches to alcoholism. These studies will make significant contributions to our understanding of etiology and pathogenesis of alcoholism.