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

描述（由申请人提供）：呈现与先前学习相关的线索，可以引发学习记忆的检索。检索到的记忆在被重新整合成长期存储之前是不稳定的。虽然不稳定，但记忆可以被破坏，这样以前由记忆支持的行为就会被显著改变或根除。药物成瘾是由多种因素决定的，但成瘾行为形成和维持的一个主要病因是药物相关记忆，这是药物相关线索和药物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，肾上腺素能拮抗剂心得安（propranolol）与线索引发的药物强化学习记忆检索相结合，可以导致再巩固（DoR）的中断，这可以通过药物强化行为的衰减/消除来证明。我们最近完成了一项NIDA资助的r21研究，首次在可卡因依赖（CD）患者中显示，在一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/装备）后给予40毫克普萘洛尔与安慰剂，在24小时后进行的CCE测试中，其渴望和线索反应性明显减弱。一周后的CCE测试显示，与安慰剂组相比，心得安组的渴望减弱仅呈趋势水平。虽然没有足够的能力这样做，我们在一周的随访期间初步检查了可卡因的使用情况。服用心得安的参与者确实报告了可卡因使用量的大幅减少，但这种差异在统计上并不显著。虽然这些发现令人鼓舞，但开发基于dor的治疗的关键下一步是增强在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)加倍普萘洛尔药物CCE检索会话的次数和(b)增加普萘洛尔的剂量来增强DoR效应。因此，3组CD与会者将接受两次CCE会议，每次会议间隔24小时。这两项研究都是在参与者住院期间进行的。一组（PBO）将在每次CCE治疗后接受安慰剂，而第二组（40PP）和第三组（80PP）将分别接受40毫克和80毫克心得安。参与者将在出院后2天、1周、3周和6周返回，并将进行CCE会议，以评估DoR对渴望和对熟悉和新的可卡因线索的提示反应的维持/推广效应。在随访期间，参与者还将每周评估3次可卡因使用情况（自我报告和尿液药物筛查）。预计40PP组和80PP组，相对于PBO，在随访期间会有更大的渴望、线索反应性和可卡因使用的衰减。另外，这些效果在80PP组会比40PP组更大。这些期望的确认将为临床试验奠定基础，从而提高其结果的特性

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.