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，旨在评估可卡因成瘾的潜在药物疗法，并根据SPIRCAP RNA DA 00-001编写。这一系列研究将检验由首席研究员F·艾薇·卡罗尔博士开发的可卡因的新型3-苯基托烷类似物。这些化合物具有暗示药物治疗价值的特性；它们有效和选择性地与多巴胺转运蛋白结合，多巴胺转运蛋白是公认的参与可卡因行为影响的部位，并且起效慢，持续时间长，这些特性被认为是有效治疗可卡因成瘾药物所必需的。项目3将检验一组这些化合物对大鼠静脉注射可卡因自我给药的影响，并为灵长类自我给药研究(项目4)提供信息。我们的实验室在这方面经验丰富，目前正在进行这样的研究。项目3的第一个目标是评估选定的六种化合物(每种两剂)的推广能力，以最大限度地减少对反应率的干扰(从项目2获得的结果)。我们将研究这些化合物是否改变了可卡因自我给药的维持。结果将导致选择四种化合物在项目4中进行测试。选择的化合物将使可卡因剂量反应函数向下移动，因为这是根据在动物身上获得的自我给药数据，有效治疗可卡因成瘾的药物治疗剂的最佳指标。项目3的第二个目标是检查两种化合物对可卡因引起的可卡因反应在杠杆按压反应消失后恢复反应的影响。这个程序是我们实验室建立并运行的一个很好的“复发”模型。项目3的目标2的具体结果是确定复合区块是否导致恢复或导致恢复。从这一目标获得的数据将与项目2和4的结果结合使用，为继续进行人体研究的决定提供依据。(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).