The neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha, 5alpha-P) is a potent modulator of the GABA (A) receptor complex (GRC). Endogenous 3alpha,5alpha-P can reach levels that are within the range of concentrations previously shown to potentiate the in vitro action of GABA at the GRC, which suggests that it may be a physiologically significant neuromodulator. Consistent with this speculation, recent work using genetic animal models found that lower endogenous levels of, or decreased sensitivity to, 3alpha,5alpha-P may be correlated with ethanol withdrawal hyperexcitability, Therefore, the present proposal will test the hypothesis that genetic differences in ethanol withdrawal hyperexcitability are due, at least in part, to modulatory effects of endogenous GABA-agonist neuroactive steroids. Based on progenitor differences in 3alpha, 5alpha-P sensitivity, the BXD Recombinant Inbred strains will be tested to (1) determine genetic correlations between 3alpha,5alpha-P sensitivity and/or biosynthesis with hyperexcitability during ethanol withdrawal and (2) identify significant quantitative trait loci (QTL) for these traits. Sensitivity of the GRC to 3alpha,5alpha-P, measured by GABA-stimulated chloride uptake, and behavioral sensitivity to 3alpha,5alpha-P will be evaluated in ethanol-naive and ethanol-withdrawing mice. The proposed behavioral tests will evaluate anxiolytic effects and locomotor activity (measured on an elevated plus maze), ataxic effects (measured by rotarod performance), muscle relaxation (measured in a test of grip strength) and anticonvulsant effects (measured by tail infusion of the convulsant pentylenetetrazol). In addition, the effect of chronic ethanol on a specific steroid biosynthetic pathway will be examined. The first goal for the proposed work is to determine 3alpha,5alpha-P responses to chronic ethanol, map QTL for these traits and compare to those for other ethanol related traits. This focus on gene mapping is consistent with the overall goal of the Center, which is to identify risk and protective genes for neuroadaptive responses to alcohol. A long term related objective is to clarify our basic understanding of how deleterious responses to chronic alcohol (i.e., physical dependence leading to withdrawal seizures) are regulated at the genetic level. The second goal is to gain information which would hopefully lead to the development of more efficient treatments for alcohol abuse and alcoholism. Since GABA-agonist neuroactive steroids are effective against seizures with an anticonvulsant profile reminiscent of the clinically useful benzodiazepines, several pharmacological effects of 3alpha,5alpha- P will be examined in order to evaluate the therapeutic potential of neuroactive steroids or their analogs in the treatment of alcohol dependence.
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