Preventing Cocaine Relapse: Developing Pharmacotherapies

描述（由申请人提供）：可卡因滥用仍然是一个重大的公共卫生问题。治疗后可卡因使用的复发率仍然令人沮丧的高，即使先进的行为和认知复发预防疗法的出现。确定一种有效的药理学辅助剂可能是必要的，以进一步降低可卡因复吸率。 本提案的具体目的是证明阿立哌唑是可卡因的有效“抗复发”药物，并可能确定其发挥这种作用的行为机制（即，阿立哌唑减弱了可卡因的初始剂量的辨别作用，从而减少了随后的药物自我给药）。为了实现这一目标，我们将首先通过在阿立哌唑维持期间施用递增剂量的口服和鼻内可卡因剂量并监测生理和行为反应来确定可卡因-阿立哌唑组合的安全性和耐受性（Exp. 1）。然后，我们将证明长期阿立哌唑治疗减弱可卡因的辨别刺激效应（实验1）。2）。药物的区别刺激效应可能涉及药物服用行为的复发，因为初始或引发剂量（即，一个失误）作为一个区别刺激的功能，信号的可用性更多的可卡因。最后，Exp。3将证明可卡因的引发剂量（即，失效）增加了随后的可卡因服用，使用设计用于模拟复发的新型自我给药程序，并且阿立哌唑减弱了这种作用。 选择阿立哌唑进行研究，因为它是多巴胺（DA）D2和5-羟色胺（5-HT）5-HT 1A受体的有效部分激动剂。辅酶A被认为通过阻断单胺转运蛋白（例如，DA和5-HT）。部分激动剂可能是一种新的和有效的手段，以防止复发可卡因使用，因为理论上他们应该有激动剂和拮抗剂的治疗优势。与这一观点相一致，我们实验室最近进行的一项实验结果表明，急性给药阿立哌唑显著减弱了d-苯丙胺在人体中的辨别刺激和主观效应。我们不知道任何已发表的报告，其中可卡因的影响进行了评估后，人类与阿立哌唑预处理。 拟议的研究将提供关于阿立哌唑作为可卡因依赖的假定“抗复发”药物的疗效的初步临床信息。开展拟定的对照实验室研究将提供重要信息（例如，合适的剂量），这将指导后续临床试验的设计。减少吸毒复吸很重要，因为静脉注射可卡因可能与获得性免疫缺陷综合征（A.I.D.S.）风险增加有关。

DESCRIPTION (provided by applicant): Cocaine abuse continues to be a significant public health concern. Relapse rates to cocaine use after treatment remain discouragingly high even with the advent of sophisticated behavioral and cognitive relapse prevention therapies. Identifying an effective pharmacological adjunct will likely be necessary to further reduce cocaine relapse rates. The specific aim of this proposal is to demonstrate that aripiprazole is an effective "anti-relapse" medication for cocaine, and possibly determine the behavioral mechanism by which it exerts this effect (i.e., aripiprazole attenuates the discriminative effects of priming doses of cocaine thereby reducing subsequent drug self-administration). To accomplish this aim, we will first determine the safety and tolerability of cocaine-aripiprazole combinations by administering ascending doses of oral and intranasal cocaine doses during aripiprazole maintenance, and monitoring physiological and behavioral responses (Exp. 1). We will then demonstrate that chronic aripiprazole treatment attenuates the discriminative-stimulus effects of cocaine (Exp. 2). The discriminative-stimulus effects of drugs may be involved in relapse to drug taking behavior in that the initial or priming dose (i.e., a lapse) functions as a discriminative stimulus that signals the availability of more cocaine. Finally, Exp. 3 will demonstrate that a priming dose of cocaine (i.e., a lapse) increases subsequent cocaine taking using a novel self-administration procedure designed to model relapse, and that aripiprazole attenuates this effect. Aripiprazole was chosen for study because it is a potent partial agonist at the dopamine (DA) D2 and serotonin (5-HT) 5-HT1A receptors. Cocaine is thought to exert its effects by blocking monoamine transporters (e.g., DA and 5-HT). Partial agonists may represent a novel and effective means to prevent relapse to cocaine use because theoretically they should have the therapeutic advantages of both an agonist and an antagonist. Consistent with this notion, the results of a recent experiment conducted in our laboratory suggest that acutely administered aripiprazole significantly attenuates the discriminative-stimulus and subjective effects of d-amphetamine in humans. We are unaware of any published reports in which the effects of cocaine were assessed in humans following pretreatment with aripiprazole. The proposed research will provide the initial clinical information regarding the efficacy of aripiprazole as a putative "anti-relapse" medication for cocaine dependence. The conduct of the proposed controlled laboratory studies will provide important information (e.g., appropriate doses) that will guide the design of a subsequent clinical trial. Reducing relapse to drug use is important because intravenous abuse of cocaine may be associated with increased risk of acquired immunodeficiency syndrome (A.I.D.S.).