EXCEED THE SPACE PROVIDED. Administration of neurosteroids [allopregnanolone (ALLO) or 5a-dehydroprogesterone (5aDHP)] potently modulates neuronal activity by post-translationally regulating GABA or glutamate receptor functions or by changing specific protein gene expression. Since ALLO and SaDHP are the two most important neuroactive steroids synthesized in brain in a region-specific manner, a major goal of the present application is to obtain a decisive demonstration of whether brain ALLO and SaDHP are putative natural modulators for central GABAergic and perhaps also glutamatergic transmission. We have recently reported that, in patients with severe depression, there is a decrease in the CSF levels of ALLO, which is normalized by treatment with drugs (i.e., fluoxetine) that improve psychopathology (Uzunova et al., 1998). The mechanism by which fluoxetine and other SSRIs normalize ALLO CSF levels appears to involve a direct stimulation of 3-a HSOR, the enzyme that favors the reduction of SaDHP to ALLO (Griffin and Mellon, 1999). As mentioned above, in rats and mice fluoxetine selectively increases ALLO and fails to change or even decreases brain 5aDHP content (Uzunov et al., 1998; Matsumoto et al., 1999). To establish a model to study the consequences of a deficiency of endogenous 5aDHP or ALLO in the various behavioral manifestationsof mood disorders present in depressed patients, we will use socially-isolated mice as a model. These mice exhibit increased anxiety, aggressive behavior, and decreased response to the administration of a GABA- mimetic drug. Furthermore, neurochemically, these mice express a marked decrease of both ALLO and SaDHP expression, which is selectively normalized by fluoxetine in doses that reduce behavioral abnormalities. On the basis of these data, we can entertain the following hypotheses: Brain synthesizes a significant amount of neuroactive steroids (ALLO and SaDHP) that are relevant to the physiological modulation of GABAergic neuronal function. We also hypothesize that brain ALLO content, through its allosteric modulatory action on GABAA receptors, and that SaDHP content, through its regulatory action on gene transcription (GABAA or glutamate receptor subunit expression), play a role in the regulation of animal and/or human mood and behavior. These hypotheses will be tested by determining: 1) brain region-specific differences in ALLO and SaDHP turnover rate; 2) molecularmechanisms responsible for changes in ALLO and SaDHP turnover rate in socially-isolated mice; and ; 3) if social isolation-elicited brain decreases of ALLO and/or SaDHP alter GABAA or glutamate (AMPA or NMD A) receptor subunit expression. The results of these studies may enable us to design specific drugs that differentially affect neurosteroidogenic enzymatic activities and therefore provide more efficacious treatment of mood disorders. PERFORMANCE SITE ========================================Section End===========================================
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