AAS and the Neurobiology of Social Behaviors

AAS 和社会行为的神经生物学

• 批准号: 7032334
• 负责人: ANN S. CLARK
• 金额: $ 35.13万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032334
• 关键词: GABA receptor; aggression; androgen analog; androgen inhibitor; androgen receptor; behavioral /social science research tag; developmental neurobiology; dosage; drug abuse; drug adverse effect; estrogen inhibitor; estrogen receptors; gamma aminobutyrate; gender difference; hormone regulation /control mechanism; laboratory mouse; prosencephalon; psychopharmacology; receptor binding; social behavior; substance abuse related behavior

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.

描述（由申请人提供）：合成代谢 - 源源类固醇（AAS）是最初设计用于治疗用途的睾丸激素的合成衍生物。尽管今天在临床上继续使用AAS，但低治疗剂量的AAS的医疗益处与与越来越多的娱乐用户自我管理的过度剂量相关的潜在健康风险形成鲜明对比。虽然刻板印象的AAS使用者是成年男性，但最近的研究表明，AAS滥用的最快增加是女性。尽管有这一事实，但很少有研究评估了AAS对女性行为的影响，并且没有进行研究以测试AAS是否通过男性和女性大脑中相同的信号传导机制作用。侵略性提高是AAS使用的最常见的心理效应。雄激素和雌激素受体（AR和ER）介导的信号对于在两性中的先天侵略表达至关重要：但是AR和ER在介导AAS诱导的攻击中的作用尚不清楚。 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).重要的是，这项研究将是第一个在雄性和雌性小鼠中比较和对比这些影响的研究。由前脑γ-氨基丁酸A型（GABAA）受体介导的神经传播是先天侵略的表达所必需的。我们已经表明，AAS治疗改变了前脑GABAA受体的表达和功能，但在男性和雌性小鼠中的作用却有所不同。该提案的第二个目标是确定前脑区域中AAS依赖性GABAA受体变化的剂量反应特征对于表达侵略的表达至关重要，AR和ER信号在介导这些变化中的重要性，并进一步确定AAS对雄性小鼠和雌性小鼠之间对前脑GABAA受体的影响如何不同。迄今为止，已经合成了60多个AA，其雌激素和雄激素特性各不相同。这些实验的数据将对理解这些滥用AA的影响对不良侵略产生的影响具有重要意义，以及它们是否在男性和女性中的作用有所不同。这些数据还将提供有关AAS引起突触传播变化的机制的重要新信息，这些机制可能导致AAS诱导的雄性和女性大脑的侵略性。这些数据可能不仅与了解AAS的影响有关，还与其他通过GABA能途径作用的滥用药物有关。