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：（申请人摘要） 该项目的总体目标是评估行为影响 合成代谢雄激素类固醇 (AAS) 并了解其背后的原理 这些变化的机制。 将采用完整的雄性大鼠模型 为了提供行为和神经解剖学的经验数据 AAS 滥用的后果。 AAS 通常分为三种不同类别 滥用：睾酮酯、19-去甲睾酮酯和 17-α-烷基化雄激素。 AAS 用户通常会“堆叠”这些药物 （即，一起使用几个）。 然而，由于对大鼠知之甚少 除了睾酮之外，AAS 的行为影响，我们建议测试 每个类别中分别有一个 AAS。 睾酮酯会 是丙酸睾酮（TP），19-去甲睾酮酯将是 诺龙 (ND) 和 17-α-烷基化雄激素将是康力龙 (ST)。 所有这些都是经常被滥用的 AAS。 前两个目标将调查两个 人类用户经常报告的行为障碍：攻击性和 昼夜节律。 第一个目标将确定上下文线索的作用 在暴露于 TP、ND 或 ST 期间刺激攻击性，以及这些是否 在退出 AAS 期间，同样的提示也有效。 第二个目标将 通过测量车轮运转来测试 AAS 对昼夜节律的影响 AAS 曝光期间 12:12 LD 中的活性、相位反转和持续黑暗 以及 AAS 撤回期间。 因为 AAS 滥用在青少年中呈上升趋势 对于男性，第三个目标中提出的实验将评估 AAS 对昼夜节律、攻击性和生殖功能的影响 青春期前后的雄性大鼠。 我们还将检查行为影响是否 在这个发育的关键时期暴露的 AAS 是可逆的或 永恒的。 评估这些 AAS 是否与雄激素结合的能力 受体与其行为效应有关，第四个目标将评估 TP、ND、ST对脑内雄激素受体的结合特性。 第五个目标将跟进我们的新发现，即长期暴露于 AAS 导致特定脑核中可检测细胞的损失。 我们将 确定经 TP 处理的雄性细胞是否发生检测能力丧失 在神经元或神经胶质细胞中，以及受影响的细胞是否含有雄激素受体。 双标记免疫荧光和共聚焦显微镜将用于 结合体积/尺寸分析来研究细胞 受影响细胞的特征。 这些研究将有助于理解 AAS 滥用对机器人成人和青少年行为的影响，并将 描述 AAS 对大脑影响的可能机制。