Hippocampus and Relapse Associated with Drug Addiction

描述（由申请人提供）：在长期禁欲后，与重新寻求毒品和吸毒行为相关的复发是一个严重的社会问题。这个问题在理解支持复发的过程和开发可以减轻或预防复发的药物方面提出了挑战。海马CA 3区的模式完成功能已被证明在基于对象的线索记忆任务的背景下，但到目前为止还没有被检查的背景下，基于对象的线索诱导复发的药物寻求行为。此外，先前关于海马的视觉提示记忆功能的工作已经证明了在将阿片样物质拮抗剂输注到CA 3中之后图案完成的破坏，这为管理复发和药物寻求行为提供了潜在的新治疗靶点。因此，该提议将测试以下假设：涉及海马CA 3编码和其中的阿片信号传导的模式完成过程是基于对象的线索的子集引起药物寻求/偏好复发的能力的基础。这个建议的第一个目的是使用一个变种的条件性位置偏好任务，其中可用的基于对象的线索的数量进行参数调整，以评估线索诱导的吸毒行为复发的模式完成的作用。此外，这一目标将为模式完成过程提供额外的证据，并为管理复发提供潜在的治疗靶点，因为它将确定是否将纳洛酮全身给药或局部输注到CA 3区域会破坏可卡因的线索诱导复发。该提议的第二个目的将提供额外的证据，证明在线索诱导的药物寻求复发期间CA 3中的模式完成。Arc mRNA表达的原位杂交分析将用于绘制CA 3中的神经激活以及通过大鼠暴露于药物相关线索的子集与暴露于所有线索而激活相同神经元集合的程度。这些目标的成功完成，应导致识别新的，具体的，神经基板，可能有针对性的未来行为和药理学操纵，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.