The Role of Allopregnanolone and Ethanol in Brain

本研究计划的目的是研究异孕酮在乙醇在大脑中的作用。这一建议建立在先前的工作基础上，该工作建立了异孕酮作为乙醇的一些行为和电生理效应的调节剂。急性乙醇暴露能够诱导大鼠皮质中生理相关的异孕酮水平。体内和体外模型将用于测试乙醇对外周类固醇来源以及中枢胶质神经类固醇来源的影响。神经胶质细胞是脑内神经类固醇生物合成的主要部位。此外，克隆的类固醇生物合成酶将用于直接测试乙醇对神经类固醇生物合成途径的影响。综上所述，这些研究将确定乙醇诱导的神经类固醇的来源，并指出用于诱导神经类固醇水平的机制。有证据表明，gaba能神经类固醇异孕酮在调节乙醇饮酒行为的获得、乙醇耐受性和一些乙醇诱导的行为中起重要作用。通过揭示乙醇影响皮质异孕酮水平的机制，该领域将对酒精中毒及其相关疾病的潜在生物学基础有更深入的了解。此外，由于异孕酮是一种内源性化合物，它是一种非常可行的治疗干预目标，没有许多精神活性药物治疗特征的过多副作用。

The objective of this research proposal is to examine the role of allopregnanolone in ethanol action in the brain. This proposal builds on previous work that establishes allopregnanolone as a modulator of some behavioral and electrophysiological effects of ethanol. Acute ethanol exposure has the ability to induce physiologically relevant allopregnanolone levels in rat cortex. In vivo and in vitro models will be used to test ethanol's effect on peripheral steroid sources as well as central glial neurosteroid sources. Glia are the main site of neurosteroid biosynthesis in the brain. Furthermore, cloned steroid biosynthetic enzymes will be used to test directly the effect of ethanol on the neurosteroid biosynthetic pathway. In combination, these studies will determine the source of ethanol-induced neurosteroids as well as indicate the mechanism used to induce neurosteroid levels. There is evidence to suggest that the GABAergic neurosteroid allopregnanolone is important in modulating the acquisition of ethanol drinking behavior, tolerance to ethanol, and some ethanol induced behaviors. By uncovering the mechanism through which ethanol influences cortical allopregnanolone levels, the field will gain a greater understanding of the underlying biological basis of alcoholism and its related disorders. Also, because allopregnanolone is an endogenous compound, it is a very viable target for therapeutic intervention without the plethora of side effects the characterize many psychoactive drug treatments.