DOPAMINE PARTIAL AGONISTS AND COCAINE DEPENDENCE

多巴胺部分激动剂和可卡因依赖

• 批准号: 2713131
• 负责人: George F. Koob
• 金额: $ 19.76万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-15 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2713131
• 关键词: behavior modification; behavior test; behavioral /social science research tag; behavioral extinction; dextroamphetamine; dopamine agonists; dopamine antagonists; dopamine receptor; drug abuse chemotherapy; drug addiction; drug interactions; drug withdrawal; electrophysiology; ethology; intravenous drug abuse; laboratory rat; operant conditionings; reinforcer; self medication; statistics /biometry

DESCRIPTION: (Applicant's Abstract) Animal models exist for many components of the psychostimulant dependence cycle including the acute reinforcing effects of cocaine and amphetamine, withdrawal from these drugs and even reinstatement of responding after extinction. Basic preclinical studies have implicated brain dopamine neurotransmission in all three of these components of the psychostimulant dependence cycle. However, attempts to modify these aspects of cocaine dependence by manipulation of brain dopamine systems with agonists or antagonists have met with limited success at the clinical level prompting the search for novel means of altering dopaminergic function. Dopamine partial agonists have the unique neuropharmacological profile of having high affinity for the receptor, but low intrinsic activity. The functional consequence is that partial agonists may act as agonists in conditions of low receptor occupancy by the transmitter as, for example, in the case of denervation or depletion due to overstimulation of activity. Similarly, the same compounds may act as functional antagonists in case of high endogenous transmitter tone as may happen during intense presynaptic activity or after pharmacological stimulation (e.g. exposure to cocaine or amphetamine). Recent studies in our laboratories have shown that two partial agonists SDZ 208-911 and terguride can increase cocaine self-administration (decrease the inter-injection interval) in rat, similar to the effects observed with dopamine antagonists. Unknown. however, is the nature of the interaction of these partial agonists with the full cocaine dose-effect function and with other aspects of psychomotor stimulant dependence. The purpose of the proposed studies is to explore the effects of a wide range of dopamine partial agonists on intravenous cocaine self-administration, cocaine withdrawal and the reinstatement of cocaine self-administration after extinction. Four doses of different partial agonists will be tested in rats against full dose effect functions for cocaine and amphetamine self-administration and on a multiple schedule for food and drug (Specific Aims 1&2). The effect of dopamine partial agonists will be tested on cocaine withdrawal using locomotor activity and brain stimulation reward thresholds (Specific Aim 3) and on the reinstatement of cocaine self-administration in animals subjected to extinction of cocaine self-administration (Specific Aim 4). These studies will help elucidate the effectiveness of dopamine partial agonists with a wide range of intrinsic efficacies in modifying various phases of the natural history of psychostimulant dependence.

描述：（申请人摘要） 精神兴奋剂依赖的许多组成部分都存在动物模型 循环，包括可卡因和安非他明的急性强化作用， 戒断这些药物，甚至恢复反应后 灭绝。 基础临床前研究表明大脑多巴胺 精神兴奋剂所有这三种成分中的神经传递 依赖循环。 然而，尝试改变可卡因的这些方面 通过使用激动剂或药物操纵大脑多巴胺系统来产生依赖性 拮抗剂在临床水平上取得的成功有限 寻找改变多巴胺能功能的新方法。 多巴胺 部分激动剂具有独特的神经药理学特征，即具有高 对受体有亲和力，但内在活性低。 功能性的 结果是部分激动剂可以在以下条件下充当激动剂： 发射器对接收器的占用率较低，例如，在 由于活动过度刺激而导致去神经支配或耗竭。 同样， 在高内源性的情况下，相同的化合物可以充当功能性拮抗剂 发射器音调可能发生在激烈的突触前活动期间或之后 药物刺激（例如接触可卡因或安非他明）。 我们实验室最近的研究表明，两种部分激动剂 SDZ 208-911 和特麦角脲可以增加可卡因的自我给药（减少 注射间隔）在大鼠中，类似于观察到的效果 多巴胺拮抗剂。 未知。 然而，这是交互的本质 这些部分激动剂具有完整的可卡因剂量效应函数，并且 与精神运动兴奋剂依赖的其他方面。 目的 拟议的研究旨在探索多种多巴胺的影响 静脉注射可卡因自我给药的部分激动剂，可卡因 戒断并恢复可卡因自我给药 灭绝。 将在大鼠中测试四种剂量的不同部分激动剂 针对可卡因和安非他明的全剂量效应函数 自我管理和多重时间表的食物和药物（具体 目标 1 和 2)。 多巴胺部分激动剂的作用将在以下方面进行测试 使用运动活动和脑刺激奖励可卡因戒断 阈值（具体目标 3）和恢复可卡因 可卡因灭绝动物的自我给药 自我管理（具体目标 4）。 这些研究将有助于阐明 多巴胺部分激动剂的有效性具有广泛的内在作用 改变自然历史各个阶段的功效 精神兴奋剂依赖。