Interactions of Anabolic Steroids and Stress Hormones in the Forebrain

前脑中合成代谢类固醇和应激激素的相互作用

• 批准号: 7316590
• 负责人: LESLIE P HENDERSON
• 金额: $ 7.26万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7316590
• 关键词: Acoustics; Action Potentials; Adolescent; Adult; Aggressive behavior; Alcohols; Aminobutyric Acid; Aminobutyric Acids; Amygdaloid structure; Anabolic steroids; Anxiety; Behavior; Behavior assessment; Behavioral; Behavioral Assay; Biological Assay; Brain Stem; Cell Nucleus; Cells; Chronic; Consumption; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Dependence; Emotional; Exposure to; Female Adolescents; Fire - disasters; Foundations; Fright; Future; Gap Junctions; Generations; Goals; Hormones; Hostility; Illicit Drugs; Laboratories; Mediating; Mediator of activation protein; Mus; Neurons; Neurotransmitters; Nexus (resin cement); Numbers; Output; Pattern; Pharmaceutical Preparations; Physiological; Play; Prosencephalon; Puberty; Range; Reaction; Reverse Transcriptase Polymerase Chain Reaction; Risk-Taking; Role; School-Age Population; Self Administration; Signal Transduction; Steroids; Stress; Structure of terminal stria nuclei of preoptic region; Synaptic Transmission; System; Therapeutic Uses; Work; alcohol effect; base; biological adaptation to stress; drug of abuse; high school; human subject; interest; patch clamp; receptor; relating to nervous system; research study; response; sex; transmission process; urocortin

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.

描述（由申请人提供）：在过去的几十年中，不仅被精英运动员，而且越来越多的普通公民（最令人不安的是高中生和高中生的孩子），这些药物的非法自我管理对这些药物的非法自我管理而掩盖了合成代谢雄激素类固醇（AA）的治疗使用。与成年人一样，在青少年中使用AA与一系列行为影响有关，包括增加焦虑和对压力的反应改变。此外，AAS使用者，尤其是青少年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 /或或 /或或或或或或或或或或或或或或不含酒精的药物。前脑中Y-氨基丁酸A型（GABAA）受体介导的神经传播在焦虑表达中起着至关重要的作用，并且该神经递质系统的活性都会因AAS和酒精而改变。在前脑内，延长的杏仁核区域，包括中央杏仁核（CEA）和质质末端（BNST）的床核提供了至关重要的Nexus，可介导GABAA受体介导的GABAA受体介导的传播和焦虑的行为和焦虑的行为和焦虑。我们特别感兴趣的是探索AAS作用与酒精对皮质激素释放激素（CRH）及其与杏仁核中GABA能系统的相互作用之间的潜在相似之处。 CRH是压力反应的关键调解人，已被暗示是在寻求药物和依赖性中起着重要作用，尤其是对于酒精。此外，CEA中酒精的影响至少可以部分归因于CRH介导的GABA能传播的增强。一个关键的问题是，AAS是否还会以杏仁核中的CRH/GABAA受体系统更改，这可能会导致焦虑行为的产生和在青少年AAS使用者中增加其他非法药物的使用？该提案的目的是确定三种常见AAS的“鸡尾酒”的长期暴露是否会改变CRH或其受体在CEA和BNST中的表达。确定这种类固醇状态是否改变了CRH在这些前脑区域内调节GABA能传播的能力；为了确定该方向是否改变了声学惊吓反应，这是一种反映对CRH敏感和GABAA受体介导的行为的焦虑的行为测定。数据表明，AA会影响延长的杏仁核中GABA能传播和CRH调节，这对于描述AAS如何产生行为效应的神经基础不仅要重要，还可以为未来的实验树立基础，以确定AAS对AAS对该系统的行为是否为AS提供了较高的AAS使用，从而使AAS的使用者具有AS AS的较高的感觉，并且对AAS的使用率更高，并且对AAS的感觉具有AS AS的使用，并且对AAS的使用方式却是AS的AS，并且AAS对AAS的影响是否偏向于AAS的AS，并且对AAS的使用方式却具有AS的使用，并且对AAS的使用方式却具有AS的范围。虐待。