Interdisciplinary Medication Development for Multiple Risk Factors in Relapse

描述（由申请人提供）：长期戒断后再次使用可卡因是治疗可卡因依赖的一个重大障碍。有几个危险因素被认为是导致可卡因依赖个体重新寻求药物和吸毒行为的关键因素。人体实验室研究表明，可卡因相关线索或负面情绪刺激都能产生渴望和生理唤醒。同样，复发的动物模型（例如，操作性药物寻求行为的恢复）清楚地表明，条件提示或暴露于急性压力下，会导致有可卡因自我给药史的动物恢复可卡因寻求行为。提示和压力这两个风险因素在促进药物寻求行为方面的研究越来越多，它们代表了复发药物开发的两个最佳目标。然而，很少考虑这些触发因素在复发中的相互作用，并且几乎没有尝试在统一的项目中实施复发和复发预防的实证研究的转化方法。这个项目将建立一个跨学科的方法来研究复发的主要危险因素（压力和线索），通过使用动物复发模型和建立的人类临床实验室环境来评估药物渴望。在动物模型中，急性应激暴露（足部休克应激或社会应激）将被检查应激对条件提示（音调+光线）对先前的可卡因配对杠杆的反应的潜在影响。此外，我们将测试一种新型多巴胺部分激动剂（阿立哌唑）和谷氨酸增强剂（莫达非尼）对应激、提示和应激+提示诱导恢复的影响。与恢复实验密切平行，我们将在临床实验室环境中直接评估压力、提示和压力+提示的相互作用。具体来说，HPA轴（ACTH，皮质醇），生理（心率，血压，皮肤电导），以及对急性压力（特里尔社会压力测试）或无压力后的可卡因相关线索反应（自我报告的药物渴望）的主观反应将在可卡因依赖个体中确定。在恢复模型实验中，受试者将在压力和提示反应测试之前接受阿立哌唑、莫达非尼或安慰剂控制。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，并且阿立哌唑或莫达非尼将减轻渴望和复发。总之，该项目将：a)提供一种独特的跨学科方法，以弥合已建立的动物复发模型与临床实验室范式之间的差距，该范式将直接测试复发中的压力和线索的相互作用；b)同时评估动物模型和人类实验室中治疗可卡因成瘾的假定药物疗法。

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.