PSYCHOPHARMACOLOGY OF STIMULANTS

本申请书是为研究中心续订薪酬支援而提出的 并概述了一项为期5年的研究计划，以研究 兴奋剂的神经精神药理学。反复给药 安非他明(Amph)导致多相行为改变 包括敏感化和兴奋剂后戒断综合征 (PSWs)在啮齿动物体内。这些影响的模式随着 剂量、慢性度和戒断间隔的函数。虽然多巴胺 (DA)与这些变化有关，我们的结果表明 敏化和PSWs反映了一系列依赖时间的机制 其中DA效应只代表了一系列变化的一个方面。 因此，我们提出了几条相互关联的研究路线，重点是 不同的行为阶段和潜在的DA和非DA变化 与每一个相关联。研究的目的是系统地描述 DA反应与不同的敏化模式相关 不同慢性amph方案后的发展和持续性。 对私营部门的类似评价将强调发展议程机制 兴奋剂后抑郁的发展和明显的敏感化。 个体差异范围的易感因素 将审查响应性，并特别强调 应激反应。与时间相关的潜在过程 将评估EC DA对AMPH的响应变化，包括DA释放 在躯体树突区，摄取载体的变化，指标 突触后DA受体功能及谷氨酸能可能的作用 机械装置。我们还将扩展我们之前的研究，以确定 去甲肾上腺素和5-羟色胺系统在致敏和PSWs不同阶段的变化。 最后，我们将通过以下方式来检验这些刺激作用的普遍性 其他安非他明类药物的研究。进一步阐明其作用机制 与慢性AMPH相关的行为改变可能具有 对理解导致兴奋剂的因素的启示 上瘾和复发，以及对 这些药物的精神毒性作用。

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.