BEHAVIORAL PHARMACOLOGY OF ACUTE AND CHRONIC AMPHETAMINE

急性和慢性苯丙胺的行为药理学

• 批准号: 2012822
• 负责人: DAVID S SEGAL
• 金额: $ 31.34万
• 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/2012822
• 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.

苯丙胺（AMPH）的重复给药导致多相 一系列行为变化，包括敏感化和后 兴奋剂戒断综合征（PSWS）。 这些影响的模式各不相同 作为剂量、慢性和停药间隔的函数。 虽然多巴胺（DA）与这些变化有关，但我们的研究结果表明， 表明致敏和PSWS反映了一个时间序列- 依赖性机制，其中DA效应仅代表 变化的光谱。 因此，我们提出了几条密切相关的路线， 研究的重点是各种行为阶段和 与之相关的潜在DA和非DA变化。 为了证实和扩展我们的观察， 致敏形式和刺激诱导的细胞外 (EC)DA，研究旨在系统地表征DA 各种致敏发展模式的反应相关性 和持久性不同的慢性AMPH方案。 类似 对PSWS的评估将强调作为 刺激后抑郁症的发展和明显的敏感化。 这些数据将进一步确定改变的EC DA反应在 行为的变化，将建立时间，当机制以外的 EC DA的变化可能是负责的，并将评估关系 行为和DA反应特征的个体差异之间的关系。 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： 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。 潜在的过程有助于 致敏诱导和EC DA的时间相关变化 将评估对AMPH的反应，包括DA释放， 体树突区域，摄取载体的变化，以及 神经系统。 此外，由于明显的 EC DA和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。 我们还将扩展我们以前的研究，以确定NE的作用， 在致敏和PSWS的各个阶段的5 HT系统。 最后，AMPH效应的一般性将通过以下方式进行检查： 其他AMPH类兴奋剂的研究。 进一步阐明 慢性AMPH相关行为改变的潜在机制 可能会对理解导致 兴奋剂成瘾和复发，以及对 这些药物的精神毒性