Preventing Cocaine Relapse: Developing Pharmacotherapies

描述(申请人提供)：可卡因滥用仍然是一个严重的公共卫生问题。即使出现了复杂的行为和认知复发预防疗法，治疗后使用可卡因的复发率仍然高得令人沮丧。为了进一步降低可卡因复发率，可能有必要确定一种有效的药理辅助药物。 这项建议的具体目的是证明阿立哌唑是一种有效的可卡因“抗复发”药物，并可能确定其发挥这一作用的行为机制(即阿立哌唑减弱启动剂量的可卡因的歧视效应，从而减少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(Exp.1)。然后，我们将证明，慢性阿立哌唑治疗减弱可卡因的歧视性刺激效应(实验。2)。毒品的区别性刺激效应可能与复吸吸毒行为有关，因为初始或启动剂量(即失误)作为区别性刺激，标志着有更多的可卡因可用。最后，实验3将使用一种旨在模拟复发的新的自我给药程序证明，启动剂量的可卡因(即失误)会增加随后的可卡因摄入量，而阿立哌唑可以减弱这一影响。 选择阿立哌唑进行研究是因为它是多巴胺(DA)D2和5-羟色胺(5-HT)5-HT1a受体的有效部分激动剂。可卡因被认为通过阻断单胺转运体(如DA和5-羟色胺)发挥作用。部分激动剂可能是防止再次使用可卡因的一种新的有效手段，因为从理论上讲，它们应该同时具有激动剂和拮抗剂的治疗优势。与这一概念一致的是，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-苯丙胺对人体的歧视性刺激和主观影响。我们不知道有任何已发表的报告，在阿立哌唑预处理后评估了可卡因对人体的影响。 这项拟议的研究将提供有关阿立哌唑作为可卡因依赖的“抗复发”药物疗效的初步临床信息。进行拟议的对照实验室研究将提供重要的信息(例如，适当的剂量)，指导后续临床试验的设计。减少吸毒复发很重要，因为静脉注射滥用可卡因可能会增加获得性免疫缺陷综合征(AI.D.S.)的风险。

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.).