Prefrontal control of kappa-opioid receptor mediated stress-induced relapse.

描述（由申请人提供）：从物质使用障碍中恢复的患者复发的主要触发因素之一是暴露于压力或创伤性事件。在包括条件性位置偏爱（CPP）在内的药物寻求行为的动物模型中，暴露于压力源（包括强迫游泳或社交失败压力（SDS））导致显著的恢复 可卡因引起的CPP消失的迹象SDS而不是可卡因引发的恢复依赖于位于中缝背核（DRN）的阿片能神经元上的κ阿片受体（KORs）的激活。然而，它仍然是未知的上游，皮层区域负责控制DRN在表达的压力诱导的恢复药物寻求行为。有趣的是，DRN拥有许多来自前额叶皮层（PFC）的KOR表达区域的直接输入-这是一个以前发现在压力和寻求药物行为中起重要作用的区域。因此，该提议旨在鉴定和表征皮质-KOR参与介导可卡因寻求行为的恢复，希望更好地理解KOR系统的治疗潜力。使用逆行追踪、Fos和KOR免疫组织化学的组合，特异性目标1将首先识别皮质区域和这些区域内的KOR活性，其在由社会失败应激（SDS）诱导的可卡因CPP恢复期间负责控制DRN活性。此外，目标1将确定参与的KOR的PFC神经元的已知子集，同时投射到DRN和腹侧被盖区在CPP的恢复。然后，特定目标2将直接操纵这些连接中的KOR活性，以确定皮质-KOR在可卡因-CPP恢复中的因果作用。使用KOR的位点特异性和连接特异性病毒介导的再表达，目的2的实验将评估KOR在DRN中和DRN投射PFC神经元上的再表达拯救KOR-KO小鼠表现出的SDS恢复缺陷的能力。这个建议需要在分子，遗传，生物化学和行为技术的广泛培训，这些实验的结果将提供独特的见解参与的皮质和皮质下的KOR系统在调节压力诱导的可卡因-CPP的恢复。总的来说，这些实验旨在进一步理解KOR系统如何参与表达应激诱导的复发所需的应激和奖励途径的会聚。

DESCRIPTION (provided by applicant): One of the major triggers of relapse among patients recovering from substance use disorders is exposure to stressful or traumatic events. In animal models of drug-seeking behaviors including conditioned place preference (CPP), exposure to a stressor, including forced swim or social defeat stress (SDS), results in significant reinstatement of an extinguished cocaine-induced CPP. SDS- but not cocaine-primed reinstatement depends on activation of kappa opioid receptors (KORs) located on the serotonergic neurons of the dorsal raphe nucleus (DRN). However, it remains unknown what upstream, cortical areas are responsible for controlling the DRN during expression of stress-induced reinstatement of drug-seeking behavior. Interestingly, the DRN possesses a number of direct inputs from KOR-expressing regions of the prefrontal cortex (PFC)-an area previously found to play an important role in stress and drug-seeking behavior. This proposal therefore aims to identify and characterize the involvement of cortical-KORs in mediating reinstatement of cocaine- seeking behavior in hopes of better understanding the therapeutic potential of the KOR system. Using a combination of retrograde tract tracing, Fos, and KOR immunohistochemistry, Specific Aim 1 will first identify the cortical regions, and KOR activity within these regions, that are responsibe for controlling DRN activity during reinstatement of cocaine-CPP induced by social-defeat stress (SDS). Additionally, Aim 1 will identify the involvement of KORs on the known subset of PFC neurons that simultaneously project to the DRN and ventral tegmental area in reinstatement of CPP. Specific Aim 2 will then directly manipulate KOR activity within these connections to determine a causal role of cortical-KORs in reinstatement of cocaine-CPP. Using site- and connection-specific viral-mediated re-expression of KORs, the experiments of Aim 2 will assess the ability of KOR re-expression in the DRN and on DRN-projecting PFC neurons to rescue a deficit in SDS- reinstatement exhibited by KOR-KO mice. This proposal requires extensive training in molecular, genetic, biochemical and behavioral techniques, and the results of these experiments will provide unique insight into the involvement of the cortical and subcortical KOR systems in regulating stress-induced reinstatement of cocaine-CPP. Overall, these experiments are intended to further our understanding of how the KOR system is involved in the convergence of the stress and reward pathways that is required for expression of stress- induced relapse.