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

描述（由申请人提供）：越来越多的共识是，通过整合心理社会和药理学干预，可以改善物质使用障碍的治疗结果。目前的建议将评估b-受体阻滞剂普萘洛尔破坏可卡因线索诱导的渴望和反应的能力。支持拟议研究的理由来自两项临床前研究，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，以及临床研究表明将b-阻断剂与基于焦虑的治疗相结合可以减少PTSD症状。最近的临床前研究也为这项研究提供了重要的支持，表明b受体阻滞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。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第一个翻译人类实验室研究工作，以评估普萘洛尔给药对可卡因线索暴露引起的假定记忆过程的影响。本建议的具体目的是检查普萘洛尔与安慰剂的效果，在可卡因线索暴露的检索会话后立即给药，在随后的可卡因线索暴露测试会话期间发生的渴望和生理反应。我们假设，与安慰剂治疗的可卡因依赖（CD）个体相比，普萘洛尔治疗的CD个体在测试过程中会表现出更少的渴望和生理唤醒。我们还希望在1周随访时保持测试期间发现的任何组间差异。52名CD男性和女性将被随机分配接受急性剂量的40 mg速释普萘洛尔或安慰剂，在连续两天计划的可卡因线索暴露期的第一次后立即接受。在为期两天的测试期间，参与者将留在南卡罗来纳州医科大学的综合临床研究中心（GCRC），以防止药物使用。药物将以双盲方式给药。所有受试者将在GCRC住院治疗后一周返回接受随访提示暴露会议。渴望和生理反应将被测量之前，期间和之后的所有线索暴露会议。这项研究的令人鼓舞的发现可能会导致一个对照治疗试验，其中普萘洛尔的战略管理将作为一个多组件的线索暴露干预的一个元素。可以想象，普萘洛尔可能成为几种新型和有效的药物治疗药物之一，这些药物治疗药物增加了现有基于药物滥用的干预措施（例如，甲基苯丙胺、大麻和鸦片制剂）。与NIDA的使命一致，该项目的长期目标是通过确定治疗开发/改进的创新和新颖方法来改善药物使用障碍的治疗。公共卫生相关性：这项创新的转化研究奋进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且可能有前途的连续性药物疗法对最难治的物质使用障碍之一可卡因依赖的治疗潜力。希望这一概念验证调查的结果将导致开发一种药物治疗要素，从而增强可卡因依赖性的基于安全性的治疗的结果，并可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.