PHARMACOTHERAPIES OF COCAINE ADDICTION IN RATS

项目3是代表多个学科的一系列协调良好的研究之一，旨在评价可卡因成瘾的潜在药物治疗，并根据SPIRCAP RNA DA 00-001编写。这一系列的研究将检查新的3-苯托烷类似物的可卡因开发的主要研究者，博士F。艾薇卡罗尔。这些化合物具有暗示药物治疗价值的特性;它们有效且选择性地与多巴胺转运蛋白结合，多巴胺转运蛋白是一个公认的参与可卡因行为影响的位点，并且具有起效缓慢和持续时间长的作用，这些属性被认为是有效治疗可卡因成瘾所必需的。 项目3将检查一组这些化合物对大鼠静脉内可卡因自我给药的影响，并为灵长类动物自我给药研究（项目4）提供信息。我们的实验室在这方面经验丰富，目前正在进行此类研究。项目3的第一个目的是评估六种化合物（每种两个剂量），选择它们的能力，以最小的干扰反应率（从项目2获得的结果）的可卡因辨别线索。我们将研究这些化合物是否改变可卡因自我管理的维护。结果将导致选择四种化合物在项目4中进行测试。所选择的化合物将提供可卡因剂量反应函数的下移，因为基于在动物中获得的自我给药数据，这是用于可卡因成瘾的有效药剂的最佳指标。项目3的第二个目的是研究两种化合物对可卡因引起的反应恢复的影响，在可卡因的压力反应消失后。该程序是一个建立良好的“复发”模型，在我们的实验室建立和运行。项目3的目标2的具体成果是确定复合块是否引起恢复或导致恢复。从这一目标中获得的数据将与项目2和4的结果结合使用，以告知继续进行人体研究的决定。（项目5和6）。

Project 3 is one in the series of well-coordinated studies representing multiple disciplines aimed at evaluating potential pharmacotherapies for cocaine addiction and written in response to SPIRCAP RNA DA 00-001. This series of studies will examine novel 3-phenyltropane analogs of cocaine developed by the Principal Investigator, Dr. F. Ivy Carroll. These compounds posses properties suggestive of pharmacotherapeutic value; they bind potently and selectively to the dopamine transporter, a well- recognized site involved in the behavioral effects of cocaine, and have a slow-onset and long-duration of action, attributes believed to be necessary for effective medications for cocaine addiction. Project 3 will examine the effects of a set of these compounds on intravenous cocaine self- administration in rats and provide information for the primate self- administration studies (Project 4). Our laboratory is experienced in this procedure and is currently running such studies. The first aim of Project 3 is to evaluate six compounds (two doses each) selected for their ability to generalize to the cocaine discriminative cue with minimal disruption of response rates (results obtained from Project 2). We will examine whether these compounds alter maintenance of cocaine self-administration. Results will lead to selection of four compounds to be tested in Project 4. Compounds selected would provide a downward shift in the cocaine dose response function as this is the best indicator of an effective pharmacotherapeutic agent for cocaine addiction based on self- administration data obtained in animals. The second aim of Project 3 is to examine two compounds for their effects on cocaine-induced reinstatement of responding after extinction of lever-press responding for cocaine. This procedure, a well-establishment model of "relapse", is set- up and running in our laboratory. The specific outcomes of aim 2 of Project 3 are to determine whether the compound block-induced reinstatement or cause reinstatement. Data obtained from this aim will be used, in conjunction with results from Projects 2 and 4, to inform the decision to proceed with studies in humans. (Projects 5 and 6).