PSYCHOPHARMACOLOGY OF STIMULANTS

此申请是为延续研究所的薪金支持 科学家奖，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重复给予 安非他明（AMPH）导致多相的行为变化谱 包括致敏和兴奋剂后戒断综合征 （PSWS）在啮齿类动物中。 这些影响的模式随着时间的推移而变化很大。 剂量、慢性和停药间隔的函数。 虽然多巴胺 (DA)与这些变化有关，我们的研究结果表明， 致敏和PSWS反映了一系列时间依赖性机制 其中DA效应仅代表了一系列变化的一个方面。 因此，我们提出了几个相互关联的研究方向，重点是 各种行为阶段以及潜在的DA和非DA变化 与每一个相关。研究旨在系统地描述 DA反应与各种致敏模式相关， 在不同的慢性AMPH治疗方案后的发展和持久性。 对PSWS的类似评估将强调DA机制， 刺激后抑郁症的发展和明显的敏感化。 个体差异范围的诱发因素 将审查反应能力，特别强调以下方面的作用： 应激反应性。 可能导致与时间相关的 将评价EC DA对AMPH反应的变化，包括DA释放 在体树突区域，摄取载体的变化， 突触后DA受体功能，以及多巴胺能神经递质的可能作用 机制等我们还将扩展我们以前的研究，以确定 NE和5 HT系统在致敏和PSWS的各个阶段。 最后，刺激效应的一般性将通过 其他AMPH类药物的研究。 进一步阐明机制 与慢性AMPH相关的潜在行为变化可能 对理解促进兴奋剂的因素的影响 成瘾和复发，以及持续的超敏反应， 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.