Interdisciplinary Medication Development for Multiple Risk Factors in Relapse

描述(申请人提供)：长期戒毒后再次使用可卡因是治疗可卡因依赖的一个重大障碍。一些危险因素被认为是引发可卡因依赖者再次吸毒和吸毒行为的关键因素。人体实验室研究表明，与可卡因相关的线索或消极的情感刺激都会产生渴望和生理唤醒。同样，复吸的动物模型(例如，恢复可操作的寻药行为)清楚地表明，条件性线索或暴露于急性应激可导致有可卡因自我给药史的动物恢复可卡因寻觅行为。这两个风险因素，线索和压力，已经越来越多地被研究，关于它们促进药物寻求行为的能力，它们是复发药物开发的两个最好的目标。然而，对复发中这些触发因素的相互作用的考虑很少，几乎没有尝试在一个统一的项目中对复发和复发预防的实证研究实施转换方法。这项拟议的项目将建立一种跨学科的方法，通过使用复发的动物模型和已建立的评估药物渴求的人类临床实验室环境，来研究复发的主要风险因素(压力和线索)。在动物模型中，将检查急性应激暴露(足部电击应激或社会应激)对先前与可卡因配对的杠杆上的条件线索(音调+光)反应的增强效应。此外，我们将测试一种新的多巴胺部分激动剂(阿立哌唑)和一种谷氨酸增强剂(莫达非尼)对应激、线索和应激+线索诱导的恢复的影响。在恢复实验的同时，我们将在临床实验室环境中直接评估压力、线索和压力+线索的相互作用。具体地说，将确定可卡因依赖者的HPA轴(ACTH、皮质醇)、生理(心率、血压、皮肤电导)和对急性应激的主观反应(Trier社会应激测试)或无应激后与可卡因相关的线索反应(自我报告的药物渴求)。在恢复模型实验中，受试者将在测试压力和线索反应性之前接受阿立哌唑、莫达非尼或安慰剂对照。在动物模型和人类实验室中，我们预测压力暴露将增强对可卡因配对线索的反应，阿立哌唑或莫达非尼将减轻对可卡因的渴望和复发。总而言之，该项目将：a)提供一种独特的跨学科方法，以弥合已建立的复发动物模型与将直接测试压力和复发线索相互作用的临床实验室范例之间的差距，以及b)同时评估动物模型和人类实验室中治疗可卡因成瘾的推定药物疗法。

DESCRIPTION (provided by applicant): Relapse to cocaine use following prolonged abstinence is a significant impediment in the treatment of cocaine dependence. Several risk factors have been recognized as critical in triggering relapse to drug-seeking and drug-taking behavior in cocaine-dependent individuals. Human laboratory studies indicate that either cocaine-related cues or negative emotional stimuli can produce craving and physiological arousal. Likewise, animal models of relapse (e.g., the reinstatement of operant drug-seeking behavior) have clearly demonstrated that conditioned cues or exposure to acute stress elicits reinstatement of cocaine-seeking behavior in animals with a history of cocaine self-administration. These two risk factors, cues and stress, have been increasingly studied in regards to their ability to promote drug-seeking behavior and they represent the two best targets for relapse medication development. However, there has been minimal consideration of the interaction of these trigger factors in relapse, and almost no attempts to implement a translational approach to the empirical study of relapse and relapse prevention within a unified project. This proposed project will establish an interdisciplinary approach to study the primary risk factors for relapse (stress and cues) by using both an animal model of relapse and an established human clinical laboratory setting for assessing drug craving. In the animal model, acute stress exposure (foot shock stress or social stress) will be examined for the potentiative effects of stress on conditioned-cue (tone+light) responding on a previously cocaine-paired lever. In addition, we will test the effects of a novel dopamine partial agonist (aripiprazole) and a glutamate enhancing agent (modafinil) on stress, cue, and stress+cue induced reinstatement. In close parallel to the reinstatement experiments, we will directly assess stress, cue, and stress+cue interactions in a clinical laboratory setting. Specifically, HPA axis (ACTH, cortisol), physiological (heart rate, blood pressure, skin conductance), and subjective responses to acute stress (Trier Social Stress Test) or no stress followed by cocaine-related cue reactivity (self-reported drug craving) will be determined in cocaine-dependent individuals. As in the reinstatement model experiments, subjects will receive aripiprazole, modafinil, or placebo control prior to testing for stress and cue reactivity. In both the animal model and the human laboratory, we predict that stress exposure will potentiate responding to cocaine-paired cues and that craving and relapse will be attenuated by aripiprazole or modafinil. In summary, this project will: a) provide a unique interdisciplinary approach to bridge the gap between an established animal model of relapse with a clinical laboratory paradigm that will directly test the interaction of stress and cues in relapse, and b) simultaneously assess putative pharmacotherapies in both the animal model and the human laboratory for the treatment of cocaine addiction.