NEUROSTEROIDS AND ETHANOL INTERACTIONS

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