AAS and the Neurobiology of Social Behaviors

描述(申请人提供)：合成代谢-雄激素(AAS)是最初设计用于治疗的睾酮的合成衍生物。尽管AAS今天仍在临床上使用，但治疗剂量低的AAS的医疗益处与越来越多的娱乐使用者自行服用过量AAS所带来的潜在健康风险形成鲜明对比。虽然AAS使用者的刻板印象是成年男性，但最近的研究表明，AAS滥用人数增长最快的是女性。尽管如此，很少有研究评估AAS对女性行为的影响，也没有研究测试AAS在男性和女性大脑中是否通过相同的信号机制发挥作用。攻击性增强是使用AAS最常见的心理影响。雄激素和雌激素受体(AR和ER)介导的信号转导对于两性先天性攻击的表达是必不可少的：然而，AR和ER在介导AAS诱导的攻击中的作用尚不清楚。这项建议的第一个目标是通过使用AR和ER的药理抑制剂以及使用缺乏AR或ER(特别是ERα)功能的突变小鼠的实验，确定AAS常见滥用的鸡尾酒促进攻击作用的剂量-反应特征，AAS如何改变在诱导攻击行为中重要的线索，以及AR和ER信号在介导AAS诱发的攻击中的重要性。重要的是，这项研究将首次在雄性和雌性小鼠身上比较和对比这些影响。前脑γ-氨基丁酸A型受体(GABAA)介导的神经传递是表达先天攻击行为所必需的。我们已经证明，AAS治疗改变了前脑GABAA受体的表达和功能，但在雄性和雌性小鼠中的作用不同。本研究的第二个目标是确定AAS对攻击行为表达起关键作用的前脑区域GABAA受体变化的剂量-反应特征，AR和ER信号在调节这些变化中的重要性，并进一步确定AAS对前脑GABAA受体的影响在雄性和雌性小鼠之间的差异。到目前为止，已经合成了60多个氨基酸，它们的雌激素和雄激素特性各不相同。这些实验的数据将对理解每一种被滥用的氨基酸对不愉快的攻击性的影响，以及它们在男性和女性身上的行为是否会有所不同，具有重要的意义。这些数据还将为AAS引起突触传递变化的机制提供重要的新信息，这可能有助于AAS在男性和女性大脑中诱导攻击性。这些数据可能不仅与了解AAS的影响有关，也可能与了解其他通过GABA能通路发挥作用的滥用药物的影响有关。

DESCRIPTION (provided by applicant): Anabolic-androgenic steroids (AAS) are synthetic derivatives of testosterone originally designed for therapeutic uses. Although AAS continue to be used clinically today, the medical benefits of low therapeutic doses of AAS stand in sharp contrast to the potential health risks associated with the excessive doses self-administered by a growing number of recreational users. While the stereotypical AAS user is an adult male, recent studies indicate that the most rapid increases in AAS abuse are in females. In spite of this fact, few studies have assessed AAS effects on behavior in females, and no studies have been performed to test if AAS act through the same signaling mechanisms in the male and female brain. Heightened aggression is the most commonly described psychological effect of AAS use. Signaling mediated by androgen and estrogen receptors (AR and ER) is essential for the expression of innate aggression in both sexes: however the roles of AR and ER in mediating AAS-induced aggression are not known. The first goal of this proposal is to determine the dose-response characteristics of the aggression-promoting effects of a cocktail of commonly abused AAS, how AAS may alter cues important in eliciting aggressive behavior, and the importance of AR and ER signaling in mediating AAS-evoked aggression by experiments using pharmacological inhibitors of AR and ER and using mutant mice that lack functional AR or ER (specifically ERalpha). Importantly, this study will be the first to compare and contrast these effects in male and female mice. Neural transmission mediated by forebrain gamma-aminobutyric acid type A (GABAA) receptors is required for the expression of innate aggression. We have shown that AAS treatment alters forebrain GABAA receptor expression and function, but does so differently in male and female mice. The second goal of this proposal is to determine the dose-response characteristics for AAS-dependent changes in GABAA receptors in forebrain regions critical for the expression of aggression, the importance of AR and ER signaling in mediating those changes, and to further establish how the effects of AAS on forebrain GABAA receptors differ between male and female mice. To date over 60 AAS have been synthesized that vary in their estrogenic and androgenic properties. Data from these experiments will have important implications for understanding the effects each of these abused AAS may have on untoward aggression and if they will act differently in men and women. These data will also provide important new information on the mechanisms by which AAS elicit changes in synaptic transmission that may contribute to AAS-induced aggression in both the male and female brain. Such data may be relevant towards understanding not only the effects of AAS, but of other abused drugs that act via GABAergic pathways.