In the past several decades, the therapeutic use of anabolic androgenic steroids (AAS) has been overshadowed by illicit self-administration of these drugs, not only by elite athletes, but also by a growing number of ordinary citizens, most disturbingly junior high- and high school-age kids. As in adults, AAS use in adolescents is associated with a range of behavioral effects, including increased anxiety and altered responses to stress. In addition AAS users, and in particular adolescent AAS users, are more likely to engage in other risk-taking behaviors, including consumption of other illicit and or /addictive drugs, including alcohol. Neural transmission mediated by y-aminobutyric acid type A (GABAA) receptors in the forebrain plays a crucial role in the expression of anxiety, and activity of this neurotransmitter system is altered by both the AAS and alcohol. Within the forebrain, regions of the extended amygdala, including the central amygdaloid nucleus (CeA) and the bed nucleus of the stria terminalis (BNST) provide a crucial nexus for mediating the interactions of both the gonadal and stress hormones on GABAA receptor-mediated transmission and in the generation of stress-induced behavior and anxiety. Of particular interest to us is to explore a potential parallel between AAS actions and the known effects of alcohol on corticotropin releasing hormone (CRH) and its interactions with the GABAergic system in the amygdala. CRH is a critical mediator of the stress response and has been implicated as playing a prominent role in drug-seeking and dependence, especially for alcohol. Moreover, effects of alcohol in the CeA can be attributed, at least in part, to a CRH-mediated enhancement of GABAergic transmission. A key question is, do the AAS also alter the CRH/GABAA receptor system in the amygdala in a manner that may contribute both to the generation of anxiety behaviors and the increased use of other illicit drugs in adolescent AAS users? The goal of this proposal will be to determine if chronic exposure to a """"""""cocktail"""""""" of three commonly abused AAS alters the expression of CRH or its receptors in the CeA and the BNST of the adolescent female mice; to determine if this steroid regime alters the ability of CRH to modulate GABAergic transmission within these forebrain regions; and to determine if this regime alters the acoustic startle response, a behavioral assay for anxiety that reflects a CRH-sensitive and GABAA receptor-mediated behavior. Data demonstrating that the AAS influence GABAergic transmission and CRH modulation in the extended amygdala will be important for delineating not only the neural basis for how the AAS produce behavioral effects, but also in setting the groundwork for future experiments to determine if the actions of AAS on this system provide an underlying mechanism that predisposes adolescent AAS users to have an altered sensitivity to, and therefore a higher likelihood to use, other drugs of abuse. ? ? ?
