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

描述（由申请人提供）：在先前学习中涉及的线索的呈现可以引发对学习的记忆的检索。恢复的记忆在重新整合回长期存储之前是不稳定的。虽然不稳定，但记忆可能会被破坏，使得先前由记忆支持的行为被显著改变或根除。药物成瘾是多因素决定的，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药物管理之间频繁配对的结果。越来越多的基础神经科学研究表明，给药肾上腺素能拮抗剂普萘洛尔与药物强化学习的线索诱发记忆恢复相邻，可导致再巩固（DoR）中断，如药物强化行为的衰减/消除所示。我们最近完成了一项NIDA资助的R21研究，首次在可卡因依赖者（CD）中显示，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/随身物品）导致在24小时后进行的CCE测试期间基本上减弱的渴望和线索反应性。1周后的CCE测试仅显示普萘洛尔组与安慰剂组相比的渴望减弱的趋势水平证据。虽然没有足够的动力这样做，我们初步研究了可卡因的使用在1周的随访期间。普萘洛尔治疗的参与者确实报告了可卡因使用量的更大减少，但这种差异没有统计学意义。虽然这些发现令人鼓舞，但开发基于DoR的治疗的关键下一步是增强R21中检测到的反应抑制“信号”，并评估其持久性，普遍性和对可卡因使用的影响。我们将尝试通过（a）加倍CCE的普萘洛尔给药恢复期次数和（B）增加普萘洛尔剂量来增加DoR效应。因此，3组CD受试者将接受两次CCE，每次间隔24小时，均在受试者住院期间进行。一组（PBO）将在每次CCE后接受安慰剂，而第二组（40 PP）和第三组（80 PP）将分别接受40 mg和80 mg普萘洛尔。参与者将在出院后两天以及1周、3周和6周返回，并将进行CCE会话，以评估DoR对渴望的维持/一般化作用以及对熟悉和新可卡因线索的线索反应性。在随访期间，还将每周3次评估参与者的可卡因使用情况（自我报告和尿液药物筛查）。预期组40 PP和80 PP相对于PBO将在随访期间表现出更大的渴望、线索反应性和可卡因使用的衰减。此外，80 PP组的这些影响大于40 PP组。这些期望的确认将为临床试验奠定基础，在临床试验中， 新的药物-行为疗法可以被系统地评价。

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.