Hippocampus and Relapse Associated with Drug Addiction

描述(由申请人提供)：长期戒毒后，与重新找寻毒品和吸毒行为相关的复发是一个严重的社会问题。这一问题对理解支持复发的过程以及能够减轻或防止复发的药物的开发提出了挑战。在基于对象的线索记忆任务中，已经证明了海马区CA3亚区的模式完成功能，但到目前为止，还没有在基于对象的线索诱导的复吸毒品行为的背景下进行研究。此外，先前对海马区视觉线索记忆功能的研究表明，在CA3区注入阿片类拮抗剂后，模式完成受到干扰，为控制复发和寻求药物行为提供了潜在的新的治疗靶点。因此，这一提议将检验一种假设，即涉及海马CA3编码和阿片类信号的模式完成过程是基于对象的线索子集唤起对药物寻找/偏好的复发的能力的基础。这项建议的第一个目的是使用条件位置偏好任务的一种变体，在该任务中，可用的基于对象的线索的数量被参数调整，以评估模式完成在线索诱导的复发到寻求药物行为中的作用。此外，这一目的将为模式完成过程和控制复发的潜在治疗靶点提供额外的证据，因为它将确定全身给药或局部向CA3区输注纳洛酮是否干扰线索诱导的可卡因复发。这项建议的第二个目的将为线索诱导的药物复发期间CA3中的模式完成提供额外的证据。Arc mRNA表达的原位杂交分析将用于定位CA3中的神经激活，以及大鼠暴露于药物相关线索子集与暴露于所有线索时相同神经元群的激活程度。这些目标的成功完成应该会导致识别新的、特定的神经底物，这些底物可能是未来行为和药物操作的靶点，以更好地管理药物滥用。

DESCRIPTION (provided by applicant): Relapse associated with return to drug-seeking and drug-taking behavior after a prolonged period of abstinence represents a serious problem for society. This problem provides a challenge in terms of understanding processes that support relapse and the development of drugs that can attenuate or prevent relapse. Pattern completion functions of the CA3 subregion of the hippocampus have been demonstrated in the context of object based-cue memory tasks, but to date have not been examined in the context of object-based cue-induced relapse to drug-seeking behavior. Furthermore, prior work on visual cue memory functions of the hippocampus have demonstrated disruption of pattern completion following infusion of an opioid antagonist into CA3, providing a potential novel therapeutic target for managing relapse and drug-seeking behavior. This proposal therefore will test the hypothesis that a pattern completion process involving hippocampal CA3 encoding and opiate signaling therein underlies the ability of subsets of object-based cues to evoke relapse to drug seeking/preference. The first aim of this proposal is to use a variant of the conditioned place preference task in which the number of available object-based cues is parametrically adjusted to assess the role of pattern completion in cue-induced relapse to drug-seeking behavior. Furthermore, this aim will provide additional evidence for a pattern completion process and a potential therapeutic target for managing relapse in that it will determine whether systemic administration or local infusion of naloxone into the CA3 region disrupts cue-induced relapse for cocaine. The second aim of this proposal will provide additional evidence for pattern completion in the CA3 during cue- induced relapse to drug seeking. In situ hybridization analysis of Arc mRNA expression will be used to map neural activation in CA3 and the extent to which the same neuronal ensembles are activated by exposure of rats to a subset of drug-associated cues vs. exposure to all cues. Successful completion of these aims should lead to the identification of novel, specific, neural substrates that may be targeted for future behavioral and pharmacological manipulation to better manage drug abuse.