Steroid Regulation of Ion Channels

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DESCRIPTION (provided by applicant): Illicit use of anabolic androgenic steroids (AAS) has become an increasingly prominent health concern. While the spotlight of media attention has been on adult male elite athletes, concern over AAS self-administration in the scientific and public health communities has shifted to the growing use of these steroids by junior high- and high school-age children, especially teenage girls. Many of these adolescent users are not involved in athletics, but are concerned with body image and take the AAS to enhance their physical appearance. The 2000 US Census estimates that 0.5 to 0.8 million teenagers abuse AAS with a mean age for initiation of 15. In humans, early exposure to high levels of androgens alters the onset of puberty, reproductive competence and sexual libido. In rodents, AAS exposure, both prior to puberty and in adults, can produce not only diminished reproductive competence, but also accelerated reproductive senescence. It is particularly relevant to AAS use in adolescence that changes in pubertal onset are associated with increased long-term risks with respect to obesity, breast cancer, drug use and mental health. Moreover, previous studies suggest that long-term risks from AAS abuse are greater in women than in men, that prepubertal and pubertal adolescents are unusually sensitive to the deleterious effects of the AAS, and that many of the AAS effects elicited during adolescence may not be reversible with cessation of drug use. Neurotransmission mediated by gamma-aminobutyric acid type A (GABAA) receptors in forebrain neuroendocrine control regions plays a critical role in regulating both pubertal onset and the expression of normal adult reproductive behaviors. We have shown that chronic AAS treatment alters GABAA receptor expression and function in these regions 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 of the receptor. In the current proposal, we will take advantage of transgenic and knockout mice to determine the role of a and e subunits in AAS-mediated modulation of GABAergic transmission and neuronal activity in gonadotropin releasing hormone (GnRH) neurons that control the hypothalamic-pituitary-gonadal axis. We will also assess how posttranslational modifications of the GABAA receptor regulate allosteric modulation by the AAS and if these changes vary with age, sex and hormonal state of the animal. Our data will generate data important for understanding how these steroids alter neuronal function to produce effects on reproductive health and how their effects differ in men vs. women and adults vs. children who abuse them.