NEUROSTEROIDS AND ETHANOL INTERACTIONS

超出所提供的空间。本研究的目的是探讨内源性3 α-羟基-5 α-葡聚糖-20-酮（3cc，5a-THP）在乙醇的细胞和行为作用中的潜在作用，包括乙醇耐受性的形成。我们发现，给予大鼠乙醇可使血浆和脑中有效的GABAA受体神经活性类固醇3a，5a-THP水平升高至与乙醇相关的浓度。乙醇对大脑皮层中3 oc，5a-THP水平的影响具有时间和剂量依赖性，并且足以增强GABAA受体功能。此外，乙醇的抗惊厥作用需要神经类固醇水平的升高。乙醇的某些电生理作用。认知障碍，并有助于它的镇静作用..相反，在乙醇依赖性大鼠中，急性乙醇攻击不会改变脑中3a，5a-THP的水平，因此，可能会对乙醇诱导3a，5a-THP的作用产生耐受性。3a，5a-THP levek的乙醇诱导的丧失可能是对乙醇药理作用耐受的基础。因此，我们建议测试的总体假设，3a，5a-THP介导的乙醇在体内的药理作用。我们目前正在研究3 α，5 α-THP是否在对乙醇的抗惊厥和认知损害作用的耐受性的发展中起作用。第三个目标集中在乙醇给药后3 α，5 α-THP积累的机制。研究正在进行中，以确定乙醇是否直接改变3a，5a-THP生物合成酶的活性。初步结果表明，乙醇差异性地增加不同脑区和肾上腺中3（X，5 α-THP的生物合成。将测量乙醇对从培养的星形胶质细胞释放3 α，5 α-THP的影响。这些研究将讨论乙醇在快速时间点（秒至分钟）的影响，这些影响可能与乙醇的电生理作用相关。这些研究阐明了乙醇在中枢神经系统中作用的新机制，并解释了为什么乙醇对GABA能神经传递的影响不能通过乙醇对GABA受体的直接作用来充分解释。在扩展期，我们计划扩大我们的研究，以了解所有四种内源性GABA能神经类固醇在啮齿动物中的作用。此外，我们计划建立乙醇对神经类固醇水平的影响，在人类中发现额外的GABA能类固醇，这项调查的结果将扩大我们的知识神经类固醇在乙醇作用和乙醇耐受性的潜在作用，并可能确定新的因素参与酒精中毒的病因。性能现场=

EXCEED THE SPACE PROVIDED. The objective of this proposal is to explore the potential role of endogenous 3a-hydroxy-5a-pregnan-20-one (3cc,5a-THP) in the cellular and behavioral actions of ethanol, including the development of ethanol tolerance. We discovered that ethanol administration to rats produces an elevation in plasma and brain levels of the potent GABAA receptor neuroactive steroid, 3a,5a- THP, to pharmacologically relevant concentrations. The effects of ethanol on 3oc,5a-THP levels in cerebral cortex are time and dose dependent and sufficient to potentiate GABAA receptor function. Moreover, the elevation of neurosteroid levels is required for the anticonvulsant action of ethanol. certain electrophvsiological actions of ethanol. cognitive impairment and contributes to it's sedative effects.. In contrast, brain levels of 3a,5a-THP are not altered by acute ethanol challenge in ethanol dependent rats, therefore, tolerance may develop to the effect of ethanol on the induction of 3a,5cc-THP. The loss of ethanol induction of 3a,5a-THP levek may underlie tolerance to the pharmacological effects of ethanol. Therefore, we propose to test the overall hypothesis that 3a,5a-THP mediates pharmacological effects of ethanol in vivo. We are currently investigating if 3a,5a-THP plays a role in the development of tolerance to the anticonvulsant and cognitive - impairing effects of ethanol. The third aim focuses on the mechanisms of 3a,5oc-THP accumulation following ethanol administration. Studies are underway to determine if ethanol directly alters the activity of the 3a,5a-THP biosynthetic enzymes. Preliminary results suggest that ethanol differentially increases 3(X,5a-THP biosynthesis in various brain regions and adrenal gland. The effect of ethanol on 3oc,5a-THP release from cultured astrocytes will be measured. These studies will address the effects of ethanol at rapid time points (seconds to minutes) that may be relevant to the electrophysiological actions of ethanol. These studies are elucidating a new mechanism of ethanol action in the CNS and explain why the effects of ethanol on GABAergic neurotransmission can not be adequately explained by the direct action of ethanol at GABA^ receptors. In the extension period, we plan to expand our studies to understand the role of all four endogenous GABAergic neurosteroids in rodent. Further, we plan to establish the effect of ethanol on neurosteroids levels in humans where additional GABAergic steroids are found. The results of this investigation will extend our knowledge of the potential role of neurosteroids in ethanol action and ethanol tolerance and may identify new factors involved in the etiology of alcoholism. PERFORMANCE SITE ========================================Section End===========================================