NEUROSTEROIDS AND ETHANOL INTERACTIONS

超出提供的空间。本研究的目的是探讨内源性3a-羟基-5a-孕烷-20-酮(3cc，5a-THP)在乙醇的细胞和行为活动中的潜在作用，包括乙醇耐受性的发展。我们发现，给大鼠注射乙醇会使大鼠血浆和大脑中强大的GABAA受体神经活性类固醇3a，5a-THP水平上升到药理上的相关浓度。乙醇对大脑皮层3oC，5a-THP水平的影响具有时间和剂量依赖性，足以增强GABAA受体的功能。此外，乙醇的抗惊厥作用需要提高神经类固醇水平。乙醇的某些电生理作用。认知功能受损，并与其镇静作用有关。相反，急性乙醇刺激不改变乙醇依赖大鼠脑内3a，5a-THP的水平，因此，耐受性可能发展为乙醇对3a，5cc-THP诱导的影响。3a，5a-THP Levek对乙醇诱导的丧失可能是对乙醇的药理作用耐受的基础。因此，我们建议检验3a，5a-THP在体内介导乙醇药理作用的总体假设。我们目前正在研究3a，5a-THP是否在对乙醇的抗惊厥和认知损害效应的耐受性发展中发挥作用。第三个目标是研究乙醇处理后3a，5oC-THP的积累机制。目前正在进行研究，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，乙醇对不同脑区和肾上腺的3(X，5a-THP)生物合成有不同程度的促进作用。测定乙醇对培养的星形胶质细胞释放3oC，5a-THP的影响。这些研究将探讨乙醇在可能与乙醇的电生理作用相关的快速时间点(秒到分钟)的影响。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用乙醇对GABA受体的直接作用来充分解释。在延伸期，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，我们计划在发现额外的GABA能类固醇的情况下，确定乙醇对人类神经类固醇水平的影响。这项研究的结果将扩大我们对神经类固醇在乙醇作用和乙醇耐受性中的潜在作用的认识，并可能确定涉及酒精中毒病因学的新因素。表演网站========================================Section End===========================================

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===========================================