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）的治疗用途已经被这些药物的非法自我管理所掩盖，不仅是精英运动员，而且还有越来越多的普通公民，最令人不安的是初中和高中年龄的孩子。与成年人一样，青少年使用AAS与一系列行为影响有关，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。前脑中γ-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，并且该神经递质系统的活性被AAS和酒精改变。在前脑内，延伸杏仁核的区域，包括中央杏仁核（CeA）和终纹床核（BNST），为介导性腺激素和应激激素对GABAA受体介导的传递的相互作用以及应激诱导的行为和焦虑的产生提供了至关重要的联系。我们特别感兴趣的是探索AAS行动和已知的影响酒精促肾上腺皮质激素释放激素（CRH）及其相互作用与GABA能系统在杏仁核之间的潜在平行。CRH是应激反应的关键介质，并被认为在药物寻求和依赖中发挥着重要作用，特别是对酒精的依赖。此外，酒精在CeA中的作用至少部分归因于CRH介导的GABA能传递增强。一个关键的问题是，AAS是否也改变了杏仁核中的CRH/GABAA受体系统，从而可能导致青少年AAS使用者产生焦虑行为和增加使用其他非法药物？本提案的目的是确定长期暴露于三种常用AAS的“鸡尾酒”是否会改变青春期雌性小鼠CeA和BNST中CRH或其受体的表达;确定这种类固醇方案是否会改变CRH调节这些前脑区域内GABA能传递的能力;并确定该方案是否改变了听觉惊吓反应，这是一种反映CRH敏感性和GABAA受体介导行为的焦虑行为测定。证明AAS影响扩展杏仁核中GABA能传递和CRH调节的数据不仅对于描绘AAS如何产生行为效应的神经基础非常重要，而且对于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使青少年AAS使用者对以下物质敏感性改变的潜在机制也很重要：因此使用其他药物滥用的可能性更高。

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.