DOPAMINE PARTIAL AGONISTS AND COCAINE DEPENDENCE

描述：（申请人摘要） 动物模型存在的精神兴奋剂依赖的许多组成部分 包括可卡因和安非他明的急性强化作用， 从这些药物中撤出，甚至恢复反应后， 灭绝 基础临床前研究表明， 在精神兴奋剂的所有三个组成部分中的神经传递 依赖循环 然而，试图改变可卡因的这些方面， 通过激动剂操纵大脑多巴胺系统产生依赖性，或 拮抗剂在临床水平上的成功有限， 寻找改变多巴胺功能的新方法。 多巴胺 部分激动剂具有独特的神经药理学特性， 对受体的亲和力，但内在活性低。 功能 结果是部分激动剂可在以下情况下作为激动剂起作用： 低受体占用的发射机，例如，在案件中， 由于活动过度刺激而导致的去神经或消耗。 同样， 相同的化合物可以在高内源性的情况下作为功能性拮抗剂 在强烈的突触前活动期间或之后， 药理学刺激（例如暴露于可卡因或安非他明）。 我们实验室最近的研究表明，两种部分激动剂SDZ 208-911和特古利特可以增加可卡因的自我给药（减少 注射间隔），与用 多巴胺拮抗剂 未知 然而，这种相互作用的本质 这些部分激动剂具有完整的可卡因剂量效应函数， 精神刺激依赖的其他方面。 的目的 一项被提议的研究是探索多种多巴胺 静脉注射可卡因的部分激动剂，可卡因 戒毒和恢复可卡因自我管理后， 灭绝 将在大鼠中测试四种剂量的不同部分激动剂 与可卡因和安非他明的全剂量效应函数进行比较 自我给药和食物和药物的多个时间表（特定 目标1和2）。 多巴胺部分激动剂的作用将在 使用自发活动和脑刺激奖励的可卡因戒断 具体目标3）和可卡因复吸问题 可卡因消失动物的自我给药 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与广泛的内在 在修改自然历史的各个阶段的功效， 精神兴奋剂依赖

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.