Interactions of Anabolic Steroids and Stress Hormones in the Forebrain

描述（由申请人提供）：在过去的几十年里，合成代谢雄激素类固醇（AAS）的治疗用途被这些药物的非法自我给药所掩盖，不仅是精英运动员，而且越来越多的普通公民，最令人不安的是初中生和高中生。与成年人一样，青少年使用AAS会产生一系列行为影响，包括焦虑增加和对压力的反应改变。此外，AAS使用者，特别是青少年AAS使用者，更有可能从事其他冒险行为，包括消费其他非法和/或成瘾药物，包括酒精。前脑y-氨基丁酸A型（GABAA）受体介导的神经传递在焦虑的表达中起着至关重要的作用，该神经递质系统的活性受到AAS和酒精的影响。在前脑内，延伸的杏仁核区域，包括中央杏仁核（CeA）和终纹床核（BNST），在介导GABAA受体介导的性腺激素和应激激素的相互作用以及应激诱导行为和焦虑的产生中提供了重要的联系。我们特别感兴趣的是探索AAS作用与酒精对促肾上腺皮质激素释放激素（CRH）的已知作用及其与杏仁核中gaba能系统的相互作用之间的潜在平行关系。CRH是应激反应的重要中介，在药物寻求和依赖中起着重要作用，特别是对酒精。此外，酒精对CeA的影响可归因于（至少部分归因于）crh介导的gaba能传递增强。一个关键的问题是，AAS是否也会改变杏仁核中的CRH/GABAA受体系统，从而导致青少年AAS使用者产生焦虑行为和增加其他非法药物的使用？本研究的目的是确定长期暴露于三种常用的AAS的“鸡尾酒”中是否会改变青春期雌性小鼠CeA和BNST中CRH或其受体的表达；确定类固醇疗法是否会改变CRH在这些前脑区域调节gaba能传递的能力；并确定这种制度是否会改变声惊反应，这是一种反映crh敏感和GABAA受体介导行为的焦虑行为分析。证明AAS影响扩展杏仁核中gaba能传递和CRH调节的数据不仅对描述AAS如何产生行为效应的神经基础很重要，而且还为未来的实验奠定基础，以确定AAS对该系统的作用是否提供了一种潜在的机制，使青少年AAS使用者对其他滥用药物的敏感性发生改变，从而更有可能使用其他药物。

DESCRIPTION (provided by applicant): 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.