BEHAVIORAL PHARMACOLOGY OF ACUTE AND CHRONIC AMPHETAMINE

急性和慢性苯丙胺的行为药理学

• 批准号: 2116446
• 负责人: DAVID S SEGAL
• 金额: $ 34.81万
• 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/2116446
• 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.

重复施用安非他明 (AMPH) 会导致多相 一系列行为变化，包括敏化和后 兴奋剂戒断综合征（PSWS）。 这些影响的模式各不相同 深刻地作为剂量、长期性和停药间隔的函数。 尽管多巴胺 (DA) 与这些变化有关，但我们的结果 表明敏化和 PSWS 反映了一系列时间序列 依赖机制，其中 DA 效应仅代表某一方面 变化范围。 因此我们提出了几条密切相关的线路 的研究重点关注不同的行为阶段和 与每个相关的潜在 DA 和非 DA 变化。 确认并扩展我们对某些人之间分离的观察 致敏和兴奋剂诱导的细胞外变化的形式 (EC) DA，研究旨在系统地表征 DA 反应与各种敏化发展模式相关 以及不同慢性 AMPH 方案的持续性。 相似的 对 PSWS 的评估将强调作为基础的发展议程机制 刺激后抑郁症的发展和明显敏化。 这些数据将进一步定义改变 EC DA 响应在 行为改变，将建立除其他机制之外的时间 EC DA 的变化可能是造成这种情况的原因，并将评估这种关系 行为和 DA 反应概况的个体差异之间。 个体差异范围的诱发因素 将审查响应能力，特别强调 以行为、神经内分泌和 DA 为特征的应激反应 对噪音刺激的反应。 潜在的流程有助于 致敏的诱导以及 EC DA 随时间的变化 将评估对 AMPH 的反应，包括 DA 的释放 体细胞树突区域、摄取载体的变化以及 谷氨酸能机制。 另外，由于明显 EC DA 与增强的行为反应性之间的分离， 将评估突触后 DA 受体功能的几个指标。 我们还将扩展之前的研究以确定 NE 和 5HT 系统处于致敏和 PSWS 的各个阶段。 最后，AMPH 效应的普遍性将通过以下方式进行检验： 其他 AMPH 类兴奋剂的研究。 进一步阐明 慢性 AMPH 相关行为变化的机制 可能对理解影响因素有影响 兴奋剂成瘾和复发，以及对兴奋剂的持续过敏 这些药物的精神毒性作用。