EXCEED THE SPACE PROVIDED. Anabolic-androgenic steroids (AAS) are synthetic derivatives of testosterone developed for hypogonadism and treatment of wasting disorders. While still invaluable therapeutic tools, illicit use of suprapharmacological doses of AAS has overshadowed their clinical use, not only with respect to elite athletes, but also a growing number of 'ordinary citizens', and most disturbingly, an appreciable number of adolescents. Chronic AAS use in both human subjects and animal models is associated with marked behavioral changes; the most notable of which are in sexual/reproductive behaviors, aggression and anxiety. Neurotransmission mediated by 7-3minobutyric acid type A (GABAA) receptors in the forebrain plays a crucial role in the expression of all of these behaviors. Interestingly, positive mood symptoms, including euphoria, hypomania and decreased anxiety are also reported, either immediately after exposure or early in the course of AAS use. These effects are reminiscent of the actions of benzodiazepines, ethanol and neurosteroids, and suggest that some of the early positive behavioral manifestations in AAS use may also arise from allosteric modulation of forebrain GABAergic transmission. We have previously shown that chronic AAS treatment alters GABAA receptor expression and function in the basal forebrain in an age- and sex-specific manner. We have also shown that acute AAS administration rapidly alters GABAA receptor function via allosteric modulation and that this modulation depends upon subunit composition. In the current proposal, we will take advantage of a transgenic mouse strain to determine the role of the E subunit in how the AAS alter GABAergic transmission in gonadotropin releasing hormone (GnRH) neurons that control the hypothalamic-pituitary-gonadal axis and are therefore the key regulators of pubertal onset and reproductive maturation. We will take advantage of a specific GABAA receptor subunit knockout strain of mice to determine the role of the a subunits in regulating AAS modulation of neural circuits important for the expression of anxiety. Finally, we will assess how posttranslational modifications of the GABAA receptor regulate allosteric modulation by the AAS and if these changes vary with the age,sex and hormonal state. To these ends we will use whole cell patch clamp recording from acutely isolated brain slices coupled with single cell real time PCR; ultrafast perfusion to recombinant receptors in heterologous cells, and behavioral assessment (ethological elevated plus maze) for anxiolytic effects of the AAS. While the behavioral actions of the AAS are well documented, the underlying neural substrates for these effects are not well known. Our data will generate data important for understanding how these steroids alter neuronal function to produce effects on reproductive and mental health, and how their effects differ in men vs. women and adults vs. children who abuse them. PERFORMANCE SITE ========================================Section End===========================================
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