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

描述(由申请人提供)：呈现先前学习中涉及的线索可以引发对学习记忆的提取。在重新整合到长期存储中之前，取回的记忆是不稳定的。虽然不稳定，但记忆可以被破坏，使得先前由记忆支持的行为被显著改变或根除。药物成瘾是多方面决定的，但成瘾行为发展和维持的一个主要病因是药物相关记忆，它是药物相关线索和给药之间频繁配对的结果。越来越多的基础神经科学研究表明，连续使用�肾上腺素能拮抗剂心得安与线索诱导的记忆恢复药物强化学习可导致药物强化学习的再巩固(DOR)中断，如药物强化行为的衰减/消除所示(S)。我们最近完成了一项由NIDA资助的R21研究，首次在可卡因依赖(CD)人群中显示，在24小时后进行的CCE测试中，在单次可卡因线索暴露或CCE(即，在实验室环境中暴露于可卡因线索/用具)后，服用40毫克心得安与安慰剂相比，可显著减轻欲望和线索反应性。一周后的CCE测试显示，心得安与安慰剂组相比，只有趋势水平的证据表明渴望减弱。虽然动力不足，但我们在1周的随访期内初步检查了可卡因的使用情况。接受普萘洛尔治疗的参与者确实报告了更大的可卡因使用量的减少，但这种差异在统计学上并不显著。虽然这些发现令人鼓舞，但开发基于DOR的治疗的下一步至关重要的是增强在R21中检测到的抑制“信号”的反应，并评估其持久性、普适性和对可卡因使用的影响。我们将尝试通过(A)将CCE的心得安药物检索会话数增加一倍，以及(B)增加心得安的剂量来增加DOR效应。因此，3组CD参与者将接受两次CCE，每次间隔24小时。在此期间，在参与者仍在医院期间进行这两项研究。其中一组(PBO)将在每次CCE疗程后服用安慰剂，第二组(40pp)和第三组(80pp)将分别服用40 mg和80 mg心得安。参与者将在出院后两天、1周、3周和6周返回，并将接受CCE会议，以评估对渴求和对熟悉和新的可卡因线索的线索反应的维持/泛化影响。参与者还将在随访期间每周接受3次可卡因使用评估(自我报告和尿液药物筛查)。预计与PBO相比，40pp和80pp组在随访期间将证明渴望、线索反应性和可卡因使用的减弱程度更大。此外，80pp组的这些影响将比40pp组更大。对这些预期的确认将为临床试验奠定基础，在临床试验中，结果将增强 可以对新的药房行为疗法进行系统评价。

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.