Enhancing Disrupted Reconsolidation: Impact on Cocaine Craving, Reactivity & Use

加强中断的再巩固：对可卡因渴望和反应性的影响

• 批准号: 8482892
• 负责人: Michael E Saladin
• 金额: $ 43.41万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8482892
• 关键词: Abstinence; Acute; Addictive Behavior; Address; Adrenergic Antagonists; Alcohols; Attenuated; Back; Behavior; Behavior Therapy; Calendar; Cardiovascular system; Center for Translational Science Activities; Clinical; Clinical Research; Clinical Trials; Cocaine; Cocaine Dependence; Cues; Development; Dose; Double-Blind Method; Drug Addiction; Drug usage; Exhibits; Exposure to; Funding; Goals; Heart Rate; Hospitals; Hour; Human; Individual; Inpatients; Laboratories; Laboratory Study; Lead; Learning; Level of Evidence; Maintenance; Measures; Medical; Memory; Methods; National Institute of Drug Abuse; Neurosciences Research; Outcome; Participant; Patient Self-Report; Pattern; Persons; Pharmaceutical Preparations; Pharmacy facility; Phase; Physiological; Placebo Control; Placebos; Preclinical Drug Evaluation; Property; Propranolol; Randomized; Reaction; Relative (related person); Reporting; Research; Resistance; Retrieval; Signal Transduction; South Carolina; Staging; Stimulus; Testing; Thinking; Time; Treatment outcome; Universities; Urine; Visit; addiction; attenuation; base; cocaine exposure; cocaine use; craving; cue reactivity; drug use screening; expectation; follow-up; improved; learned behavior; memory process; memory retrieval; novel; public health relevance; reinforced behavior; response; therapy development; trend

DESCRIPTION (provided by applicant): Presentation of cues involved in prior learning can elicit retrieval of memory for the learning. Retrieved memories are unstable before they are reconsolidated back into long-term storage. While unstable, the memories can be disrupted such that behaviors previously supported by the memories are significantly altered or eradicated. Drug addiction is multidetermined but one major etiological factor in the development and maintenance of addictive behavior is drug-associated memories, which form as a consequence of frequent pairings between drug-associated cues and drug administration. A growing body of basic neuroscience research suggests that administration of the ¿-adrenergic antagonist propranolol contiguous with cue-elicited retrieval of memory for drug reinforced learning can lead to disruption of reconsolidation (DoR) as indicated by attenuation/elimination of drug-reinforced behavior(s). We recently completed a NIDA funded-R21 showing, for the first time in cocaine dependent (CD) persons, that administration of 40 mg propranolol vs. placebo following a single session of cocaine cue exposure or CCE (i.e., exposure to cocaine cues/paraphernalia in a laboratory setting) resulted in substantially attenuated craving and cue reactivity during a test session of CCE performed 24 hours later. A test session of CCE 1 week later revealed only trend level evidence of craving attenuation in the propranolol vs. placebo group. Although insufficiently powered to do so, we preliminarily examined cocaine use during the 1-week follow-up period. The propranolol treated participants did report a greater reduction in dollar amount of cocaine used, but this difference was not statistically significant. While thes findings are encouraging, the essential next step in the development of a DoR-based treatment is to enhance the response dampening 'signal' detected in the R21 and assess its durability, generalizability and effects on cocaine use. We will attempt to augment the DoR effect by (a) doubling the number of propranolol- medicated retrieval sessions of CCE, and (b) increasing the dose of propranolol. Accordingly, 3 groups of CD participants will receive two sessions of CCE, each separated by a 24 hr. period and both conducted while the participants remain in hospital. One group (PBO) will receive placebo following each CCE session while the second (40PP) and third (80PP) group will receive 40 mg and 80 mg propranolol, respectively. Participants will return two days, and 1, 3, and 6 weeks after discharge and will be administered a CCE session to assess for maintenance/generalization of DoR effects on craving and cue reactivity to familiar and novel cocaine cues. Participants will also be assessed 3 times weekly for cocaine use (self-report & urine drug screen) during follow-up. It is expected that groups 40PP and 80PP, relative to PBO, will evidence greater attenuation of craving, cue reactivity and cocaine use during follow-up. Also, these effects will be greater in group 80PP than 40PP. Confirmation of these expectations will set the stage for a clinical trial where the outcome enhancing properties of this novel pharmacy-behavior therapy could be systematically evaluated.

描述（适用提供）：先前学习中涉及的提示的提示可以为学习的记忆检索。在将记忆重新整合到长期存储中之前，检索的记忆是不稳定的。虽然不稳定，但可以破坏记忆，以使以前由记忆支持的行为发生了重大改变或放射性的改变。药物成瘾是多次确定的，但在加性行为的发展和维持中的一个主要病因是与药物相关的记忆，这是由于药物相关线索与药物管理之间经常配对而形成的。越来越多的基本神经科学研究表明，给予 - 肾上腺素拮抗剂普萘洛尔连续与提示诱导的记忆回收用于药物增强学习的记忆可以导致重新溶解（DOR）的破坏，这是通过衰减/消除药物释放的行为所指示的（S）。最近，我们在可卡因依赖（CD）的人（CD）中首次完成了一项NIDA资助的R21，在一次可卡因提示暴露或CCE之后，给药40毫克前丙醇与安慰剂（即，在实验室环境中的可卡因提示暴露或cce的暴露量会导致24个小时的cue cue at cue cue note cue a coue coue coue coue coue coue coue coue coue coue coue coue cou a coue and cope cou a cace and co cape and cue a coe capece capected的反应很高，并提高了24个小时的反应。 1周后，CCE的测试会议显示，趋势水平的证据证明了普萘洛尔与安慰剂组中渴望衰减的证据。尽管这样做的功能不足，但我们在1周的随访期间初步检查了可卡因的使用。普萘洛尔治疗的参与者确实报告了使用的可卡因量的减少，但这种差异在统计学上并不显着。尽管发现令人鼓舞，但基于DOR治疗的发展的下一步是增强R21中检测到的“信号”的响应减弱，并评估其耐用性，对可卡因使用的耐用性和影响。我们将尝试通过（a）加倍CCE的普萘洛尔检索会议，以及（b）增加普萘洛尔的剂量来增强DOR效应。根据每组CD参与者的说法，每个参与者将获得两个CCE，每个CCE分别为24小时。在参与者留在医院的情况下，两者进行了。在每个CCE会话之后，一个组（PBO）将接受安慰剂，而第二个（40pp）和第三（80pp）组将分别获得40 mg和80 mg普萘洛尔。参与者将在出院后两天，1、3和6周返回，并将进行CCE会议，以评估DOR对渴望和提示对熟悉和新型可卡因提示的反应性的维持/概括。随访期间，还将每周评估3次可卡因使用（自我报告和尿液药物）。可以预期，相对于PBO，组40pp和80pp将证明随访期间对渴望，提示反应性和可卡因的使用更大的衰减。同样，这些效果在80pp组中将大于40pp。确认这些期望将为临床试验奠定阶段，以增强结果的性能 可以系统地评估新型药房 - 行为疗法。