ANABOLIC ANDROGENIC STEROID EFFECTS ON BRAIN & BEHAVIOR

合成代谢雄激素类固醇对大脑的影响

• 批准号: 2467348
• 负责人: Marilyn Y MCGINNIS
• 金额: $ 22.03万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-20 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2467348
• 关键词: aggression; androgen analog; androgen receptor; androgens; animal puberty; apoptosis; behavioral /social science research tag; body physical activity; circadian rhythms; confocal scanning microscopy; drug adverse effect; drug withdrawal; immunofluorescence technique; laboratory rat; male; nerve /myelin protein; neuropathology; propionates; psychopharmacology; receptor binding; sectioning; sex behavior; testosterone

DESCRIPTION: (Applicant's Abstract) The overall goals of this project are to assess the behavioral effects of anabolic androgenic steroids (AAS) and to understand the underlying mechanisms for these changes. An intact male rat model will be employed in order to provide empirical data on the behavioral and neuroanatomical consequences of AAS abuse. Three different classes of AAS are typically abused: testosterone esters, 19-nortestosterone esters, and 17-alpha-alkylated androgens. AAS users typically 'stack' these drugs (i.e., use several together). However, since little is known in rats about the behavioral effects of AAS other than testosterone, we propose to test the of one AAS from each category individually. The testosterone ester will be testosterone propionate (TP), the 19-nortetsosterone ester will be nandrolone (ND) and the 17-alpha-alkylated androgen will be stanozolol (ST). All are commonly abused AAS. The first two aims will investigate two frequently reported behavioral disturbances in human users: aggression and circadian rhythms. The first aim will determine the role of contextual cues in stimulating aggression during exposure to TP, ND or ST and whether these same cues are effective during withdrawal from AAS. The second aim will test the effects of AAS on circadian rhythms by measuring wheel running activity in 12:12 LD, phase reversal and constant dark during AAS exposure and during AAS withdrawal. Because AAS abuse is on the rise in adolescent males, the experiments proposed in the third aim will assess the effects of AAS on circadian rhythms, aggression, and reproductive function in peripubertal male rats. We will also examine whether the behavioral effects of AAS exposure during this critical period of development are reversible or permanent. To assess whether the ability of these AAS to bind to androgen receptors is related to their behavioral effects, the fourth aim will assess the binding characteristics of TP, ND and ST on androgen receptors in brain. The fifth aim will follow up our novel finding that chronic AAS exposure results in a loss of detectable cells in specific brain nuclei. We will determine if the loss of detect ability in cells of TP-treated males occurs in neurons or glia, and if the affected cells contain androgen receptors. Double label immunofluorescence and confocal microscopy will be used in conjunction with volume/size analyses to investigate the cellular characteristics of affected cells. These studies will aid in understanding the effects of AAS abuse on behavior in bot adults and juveniles, and will delineate possible mechanisms underlying AAS effects on brain.

描述：（申请人的摘要） 该项目的总体目标是评估 合成代谢雄激素类固醇（AAS），并了解基础 这些变化的机制。 完整的男性大鼠模型将在 为了提供有关行为和神经解剖学的经验数据 AAS滥用的后果。 通常是三个不同类的AA 虐待：睾丸激素酯，19-硝基酯酯和 17-α-烷基化雄激素。 AAS用户通常“堆叠”这些药物 （即，一起使用几种）。 但是，由于在老鼠中鲜为人知 除睾丸激素以外的AAS的行为效应，我们建议测试 每个类别的一个AA的一个单独的AA。 睾丸激素酯将 是丙酸睾丸激素（TP），19-北盐酯将是 nandrolone（ND）和17-α-烷基化雄激素将是Stanozolol（ST）。 所有人通常都被滥用AAS。 前两个目标将调查两个 经常报告的人类用户行为障碍：侵略性和 昼夜节律。 第一个目标将决定上下文提示的作用 在暴露于TP，ND或ST期间刺激侵略性以及这些是 同样的提示在退出AA时有效。 第二个目标 通过测量滚轮运行来测试AAS对昼夜节律的影响 在12:12 LD中的活动，相位逆转和恒定黑暗在AAS暴露期间 在AAS撤离期间。 因为青少年的AA滥用正在增加 男性，第三个目标中提出的实验将评估 昼夜节律，侵略性和生殖功能的AA perip骨雄性老鼠。 我们还将检查行为效应是否 在这个关键时期，AAS暴露是可逆的或 永恒的。 评估这些AA与雄激素结合的能力是否 受体与其行为影响有关，第四个目标将评估 TP，ND和ST的结合特征在脑中的雄激素受体上。 第五目标将跟进我们的小说发现，即慢性AAS暴露 导致特定脑核中可检测到的细胞损失。 我们将 确定是否发生了TP治疗雄性细胞中检测能力的丧失 在神经元或神经胶质中，如果受影响的细胞含有雄激素受体。 双标记免疫荧光和共聚焦显微镜将用于 与体积/尺寸分析的结合以研究细胞 受影响细胞的特征。 这些研究将有助于理解 AA滥用对机器人和少年行为的影响，并将 描述AAS对大脑的影响的可能机制。