MECHANISMS OF ADDICTION PATHOGENESIS

ARC的这一部分的目的是研究以下因素的作用： GABA能神经传递，包括神经类固醇调节，在 大鼠乙醇自我给药的开始和维持。那里 越来越多的行为证据表明中脑边缘GABA系统 参与自愿乙醇自我管理。但有一个 我们对大脑分子机制的认识存在重大差距， 酒精的自我管理和偏好。既然我们有 先前发现的证据表明GABA a受体敏感性的改变 和皮质中的表达，我们 建议研究涉及中脑边缘系统的GABA能机制， 大脑区域后，长期乙醇自我管理。这些 研究将阐明GABA a的作用，受体功能和基因， 在控制乙醇自身给药的细胞核中的表达 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 乙醇自我给药我们计划确定是否启动和/或 乙醇自我给药的维持改变了内源性神经类固醇 合成或代谢，如果直接给予神经甾类药物， 侧脑室，或中脑边缘的大脑网站改变乙醇自我- 局以前的研究表明， 大鼠乙醇自我给药可能与性别相关 神经类固醇水平的差异。我们还发现， 对大脑皮层GABA α受体α 1亚单位表达的影响 雌鼠和雄鼠。我们建议确定性别是否调节 GABA α受体功能、表达或神经甾体代谢在脑缺血再灌注损伤中的作用 GABA能中脑边缘回路在启动或维持 乙醇的自愿消费。最后，改变的影响， 将测量乙醇自身给药时的GABA a受体表达 使用载体介导的基因传递。 本部分旨在检验乙醇 自身给药受GABA α受体功能差异影响 和/或神经类固醇水平的核杏仁核，腹 被盖区和前额叶皮层。我们预测乙醇本身- 施用将改变GABA α受体敏感性和神经类固醇 大脑中边缘回路的水平。这些变化将在 反过来，调节乙醇自我管理，并有助于 酒精成瘾的发展。我们预测， 这些系统中的差异将与神经类固醇调节相关 GAMAa受体。使用载体介导的基因转移，我们希望 能够操纵乙醇自我管理行为， 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.