PSYCHOPHARMACOLOGY OF STIMULANTS

兴奋剂的精神药理学

• 批准号: 2256511
• 负责人: DAVID S SEGAL
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-12-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2256511
• 关键词: Primates; amphetamines; auditory stimulus; behavioral habituation /sensitization; central nervous system stimulants; chordate locomotion; circadian rhythms; cocaine; dopamine; dopamine receptor; drug withdrawal; ethology; glutamates; laboratory rat; membrane transport proteins; microdialysis; neural transmission; neurochemistry; neuropharmacology; neurotransmitter transport; norepinephrine; psychological stressor; psychopharmacology; serotonin; stress

This application is for renewal of salary support by the Research Scientist Award and outlines a 5-year program of research to study the neuropsychopharmacology of stimulants. Repeated administration of amphetamine (AMPH) results in a multiphasic spectrum of behavioral changes which include sensitization and a post-stimulant withdrawal syndrome (PSWS) in rodents. The patterns of these effects vary profoundly as a function of dose, chronicity, and withdrawal interval. Although dopamine (DA) has been implicated in these changes, our results suggest that sensitization and the PSWS reflect a sequence of time-dependent mechanisms in which DA effects represent only one aspect of a spectrum of changes. Therefore we propose several interrelated lines of research which focus on the various behavioral phases and the potential DA and non-DA changes associated with each. Studies are designed to systematically characterize the DA response correlates of the various patterns of sensitization development and persistence following different chronic AMPH regimens. Similar evaluation of the PSWS will emphasize DA mechanisms underlying the development and apparent sensitization of post-stimulant depression. Predisposing factors for the range of individual differences in responsiveness will be examined with particular emphasis on the role of stress reactivity. Potential processes contributing to the time-related changes in EC DA response to AMPH will be evaluated, including DA release in somatodendritic regions, changes in the uptake carrier, indices of postsynaptic DA receptor function, and the possible role of glutamatergic mechanisms. We will also extend our previous studies to determine the role of NE and 5HT systems in the various phases of sensitization and the PSWS. Finally, the generality of the stimulant effects will be examined through studies of other AMPH-like drugs. Further elucidation of the mechanisms underlying the behavioral changes associated with chronic AMPH may have implications for understanding the factors which contribute to stimulant addiction and relapse, and the persistent hypersensitivity to the psychotoxic effects of these drugs.

本申请是为了更新研究部的工资支持 科学家奖并概述了一项为期 5 年的研究计划 兴奋剂的神经精神药理学。重复给药 安非他明 (AMPH) 会导致多相行为变化 其中包括致敏和兴奋后戒断综合征 （PSWS）在啮齿类动物中。 这些影响的模式差异很大 剂量、长期性和停药间隔的函数。 虽然多巴胺 （DA）与这些变化有关，我们的结果表明 敏化和 PSWS 反映了一系列时间依赖性机制 其中 DA 效应仅代表一系列变化的一个方面。 因此，我们提出了几项相互关联的研究方向，重点关注 不同的行为阶段以及潜在的 DA 和非 DA 变化 与每一个相关联。研究旨在系统地表征 DA 反应与各种敏化模式相关 不同慢性 AMPH 方案后的发展和持久性。 对 PSWS 的类似评估将强调作为基础的 DA 机制 刺激后抑郁症的发展和明显敏化。 个体差异范围的诱发因素 将审查响应能力，特别强调 应激反应性。 有助于时间相关的潜在过程 将评估 EC DA 对 AMPH 反应的变化，包括 DA 释放 在体细胞树突区域，摄取载体的变化，指数 突触后 DA 受体功能，以及谷氨酸能的可能作用 机制。我们还将扩展之前的研究来确定角色 NE 和 5HT 系统在敏化和 PSWS 的各个阶段。 最后，将通过以下方式检查刺激作用的普遍性： 其他 AMPH 类药物的研究。 进一步阐明机制 与慢性 AMPH 相关的行为变化可能有 对理解促进兴奋剂的因素的影响 成瘾和复发，以及对药物的持续过敏 这些药物的精神毒性作用。