Treatment Implications of Beta-blockade Effects on Memory for Cocaine Craving

描述（由申请人提供）：越来越多的人认为，通过社会心理和药物干预的整合，可以改善物质使用障碍的治疗效果。目前的提案将评估b受体阻滞剂心得安破坏可卡因线索引起的渴望和反应的能力。临床前研究表明，b阻断剂可以破坏基于恐惧的联想学习的记忆再巩固过程；临床研究表明，将b阻断剂与基于暴露的治疗相结合可以减轻PTSD症状。最近的临床前研究表明，b阻断剂可能会改变与食欲药物相关的条件反射有关的记忆再巩固过程，这也为拟议的研究提供了重要的支持。由于这些有趣的发现尚未扩展到具有潜在临床应用的人类概念验证研究，因此拟议的研究代表了首次转化人类实验室研究工作，以评估心得安对可卡因提示暴露引发的假定记忆过程的影响。本研究的具体目的是研究在可卡因线索暴露后立即服用心得安与安慰剂对随后可卡因线索暴露测试期间发生的渴望和生理反应的影响。我们假设，与服用安慰剂的可卡因依赖（CD）个体相比，服用心得安的CD个体在测试过程中会表现出更少的渴望和生理唤醒。我们还期望在测试期间发现的任何组间差异将在1周的随访中保持。52名CD男性和女性将被随机分配接受40毫克速释心得安或安慰剂的急性剂量，在连续几天的两次可卡因提示暴露后立即接受。在为期两天的测试期间，参与者将留在南卡罗来纳医科大学普通临床研究中心（GCRC），以防止药物使用。药物将以双盲方式进行。所有参与者将在GCRC住院一周后返回接受随访提示暴露。在所有线索暴露之前、期间和之后，将测量渴望和生理反应。这项研究的令人鼓舞的发现可能导致一项对照治疗试验，其中战略性心得安政府将作为多成分线索暴露干预的一个元素。可以想象，心得安可能成为几种新型有效的药物治疗辅助手段之一，增强现有药物滥用（如甲基苯丙胺、大麻和阿片类药物）暴露干预措施的治疗效果。与NIDA的使命一致，该项目的长期目标是通过确定创新和新颖的治疗开发/改进方法来改善物质使用障碍的治疗。公共卫生相关性：这项创新的转化研究将采用一种已建立的线索反应性/暴露方法来评估一种未经测试但有潜力的辅助药物治疗对最棘手的物质使用障碍之一可卡因依赖的治疗潜力。希望这项概念验证调查的结果将导致药物治疗治疗要素的发展，这将提高基于暴露的可卡因依赖治疗的结果，并推广到涉及其他滥用物质的成瘾问题。

DESCRIPTION (provided by applicant): There is growing consensus that improved treatment outcomes for substance use disorders may be achieved through integration of psychosocial and pharmacologic interventions. The present proposal will assess the ability of the b-blocker propranolol to disrupt cocaine cue-induced craving and reactivity. Supporting rationale for the proposed study comes from both preclinical studies showing that b-blocking agents can disrupt memory reconsolidation processes underlying fear-based associative learning and from clinical studies suggesting that combining b-blocking agents with exposure-based therapy may reduce PTSD symptoms. Important support for the proposed research also comes from recent preclinical studies indicating that b-blocking agents may alter memory reconsolidation processes involved in appetitive drug-related conditioning. As these intriguing findings have yet to be extended to a human proof-of-concept study with potential clinical applications, the proposed study represents the first translational human laboratory research effort to evaluate the effects of propranolol administration on the putative memory processes elicited by cocaine cue exposure. The specific aim of this proposal is to examine the effects of propranolol vs. placebo, administered immediately after a retrieval session of cocaine cue exposure, on craving and physiological responses occurring during a subsequent test session of cocaine cue exposure. We hypothesize that, compared to cocaine-dependent (CD) individuals treated with placebo, propranolol-treated CD individuals will evidence less craving and physiological arousal during the test session. We also expect that any between-group differences identified during the test session will be maintained at 1-week follow-up. Fifty-two CD men and women will be randomly assigned to receive an acute dose of either 40 mg immediate-release propranolol or placebo immediately after the first of two cocaine-cue exposure sessions scheduled on consecutive days. Participants will remain in the Medical University of South Carolina's General Clinical Research Center (GCRC) throughout the two-day testing period to prevent drug use. Medications will be administered in a double-blind fashion. All participants will return one-week after their GCRC inpatient stay to undergo a follow-up cue exposure session. Craving and physiological reactivity will be measured prior to, during, and following all cue exposure sessions. Encouraging findings from this study could lead to a controlled treatment trial in which strategic propranolol administration would serve as an element of a multi-component cue exposure intervention. Conceivably, propranolol could become one of several novel and effective pharmacotherapy adjuncts that augment the treatment outcomes achieved with existing exposure-based interventions for drug abuse (e.g., methamphetamine, marijuana and opiates). Consistent with NIDA's mission, the long-term goal of this project is to improve substance use disorders treatment through the identification of innovative and novel approaches to treatment development/refinement. PUBLIC HEALTH RELEVANCE: This innovative translational research endeavor will employ an established cue reactivity/exposure methodology to assess the therapeutic potential of an untested and potentially promising adjunctive pharmacotherapy for one of the most intractable substance use disorders, cocaine dependence. It is hoped the results of this proof-of-concept investigation will lead to the development of a pharmacotherapeutic treatment element that will enhance the outcomes of exposure-based treatment for cocaine dependence and be generalizable to addiction problems involving other substances of abuse.