The Role of Allopregnanolone and Ethanol in Brain

这项研究的目的是研究别孕烯醇酮在大脑中乙醇作用的作用。这项建议建立在以前的工作，建立别孕烯醇酮作为乙醇的一些行为和电生理效应的调制器。急性乙醇暴露有能力诱导大鼠皮质中生理相关的别孕烯醇酮水平。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央胶质神经类固醇来源的影响。胶质细胞是脑内神经甾体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。结合起来，这些研究将确定乙醇诱导的神经类固醇的来源，以及指示用于诱导神经类固醇水平的机制。有证据表明，GABA能神经甾体别孕烯醇酮在调节乙醇饮酒行为、乙醇耐受和一些乙醇诱导行为的获得中是重要的。通过揭示乙醇影响皮质别孕烯醇酮水平的机制，该领域将更好地了解酒精中毒及其相关疾病的潜在生物学基础。此外，由于别孕烯醇酮是一种内源性化合物，它是一种非常可行的治疗干预靶点，而没有许多精神活性药物治疗所特有的过多副作用。

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.