BEHAVIORAL PHARMACOLOGY OF ACUTE AND CHRONIC AMPHETAMINE

急性和慢性苯丙胺的行为药理学

• 批准号: 2116447
• 负责人: DAVID S SEGAL
• 金额: $ 27.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-06-29 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2116447
• 关键词: amphetamines; behavioral habituation /sensitization; behavioral medicine; cocaine; depression; dopamine; dopamine receptor; drug abuse; drug addiction; drug withdrawal; experimental brain lesion; glutamates; high performance liquid chromatography; laboratory rat; microdialysis; neurochemistry; neurotoxins; neurotransmitter metabolism; norepinephrine; psychopharmacology; serotonin

Repeated administration of amphetamine (AMPH) results in a multiphasic spectrum of behavioral changes which include sensitization and a post- stimulant withdrawal syndrome (PSWS). 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 closely related lines of research which focus on the various behavioral phases and the potential DA and non-DA changes associated with each. To confirm and extend our observations of a dissociation between some forms of sensitization and stimulant-induced changes in extracellular (EC) DA, 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. These data will further define the role of altered EC DA response in the behavioral changes, will establish times when mechanisms other than changes in EC DA might be responsible, and will evaluate the relationship between individual variations in the behavioral and DA response profiles. Predisposing factors for the range of individual differences in responsiveness will be examined with particular emphasis on the role of stress reactivity characterized by the behavioral, neuroendocrine and DA responses to noise stimulation. Potential processes contributing t the induction of sensitization, and the time-related changes in EC DA response to AMPH will be evaluated, including DA release in somatodendritic regions, changes in the uptake carrier, and the role of glutamatergic mechanisms. In addition, because of the apparent dissociation between EC DA and the enhanced behavioral responsiveness, several indices of post-synaptic DA receptor function will be assessed. 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 AMPH effects will be examined through studies of other AMPH-like stimulants. 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.

反复服用安非他明(Amph)导致多相 包括敏感化和后遗症在内的一系列行为变化 兴奋剂戒断综合征(PSWs)。这些影响的模式各不相同 在很大程度上是剂量、慢性化和戒断间隔的函数。 尽管多巴胺(DA)与这些变化有关，但我们的结果 暗示敏化和PSWs反映了一系列的时间序列- DA效应只代表一个方面的依赖机制 变化的光谱。因此，我们提出了几条密切相关的路线 集中在不同的行为阶段和 与每一项相关的潜在DA和非DA变化。 来证实和扩展我们的观察结果，即 细胞外的敏化形式和刺激剂诱导的变化 (欧共体)DA，旨在系统地描述DA的特征 敏感化发展的不同模式的反应相关性 以及遵循不同的慢性AMH方案的持久性。类似 对PSWs的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。 这些数据将进一步定义改变的EC DA反应在 行为变化，将建立时间，当机制不是 欧共体DA的变化可能是责任所在，并将评估这种关系 在行为和DA反应特征的个体差异之间。 个体差异范围的易感因素 将审查响应性，并特别强调 以行为、神经内分泌和多巴胺为特征的应激反应 对噪音刺激的反应。潜在的进程对 敏化的诱导和EC DA的时间相关变化 将评估对AMPH的反应，包括在 躯体树突状细胞区域、摄取载体的变化及其作用 谷氨酸能机制。此外，由于明显的 EC DA和增强的行为反应之间的分离， 将评估突触后DA受体功能的几个指标。 我们还将扩展我们之前的研究，以确定NE和 5-羟色胺系统在敏化的不同阶段和PSWs。 最后，我们将通过以下方法来检验amph效应的一般性 其他安非他明类兴奋剂的研究。进一步澄清 慢性AMPH相关行为改变的潜在机制 可能对理解促成这些因素的 兴奋剂成瘾和复发，以及对 这些药物的精神毒性作用。