Endogenous Opioid Mediation of Stress and Drug Reward

描述（由申请人提供）： 释放的内源性阿片肽调节痛觉、生理应激反应和奖赏途径。因此，内源性阿片类药物被认为是对压力的行为反应以及药物自我给药的关键调节剂。这项建议将评估内源性κ阿片系统在调解压力和药物奖励的行为反应中的作用。在这个提议中，我们将进行一系列的行为实验，将小鼠暴露于强迫游泳试验，诱导内源性强啡肽释放介导的应激反应。C57 B1/6小鼠的初步结果显示，由强迫游泳试验诱导的轻度应激产生不动性和甩尾潜伏期的增加，其被预先施用κ阿片样物质拮抗剂nor-BN 1阻断。此外，在暴露于强迫游泳应激源的野生型小鼠中观察到游泳不动性和甩尾潜伏期的增加，但在缺乏强啡肽基因产物的同窝小鼠中没有观察到。未来的研究计划，以表征内源性阿片肽释放的游泳应激，以及参数分析，以充分表征内源性κ阿片系统介导的应激的组成部分。此外，这些研究将被扩展到研究应激诱导的内源性κ阿片活性在对奖励药物的反应中的作用。初步证据表明，先前暴露于强迫游泳应激的小鼠诱导了对可卡因的条件性位置偏好反应的增强。与此相反，小鼠预处理与nor-BNI或缺乏强啡肽基因产物之前，强迫游泳并没有表现出应激诱导的增强可卡因条件性位置偏爱。未来的研究与强啡肽野生型和基因敲除小鼠的计划，其中的压力效应的持续时间和强迫游泳压力对药物奖励的影响的参数分析进行检查，通过测量可卡因和海洛因的条件性位置偏好。总之，预计该数据集将表征对内源性κ阿片样物质系统作用调节的行为应激和药物奖励的反应。更好地了解压力和内源性kappa系统之间的关系，可能会导致新的见解压力诱导的药物滥用复发，以及提供一个新的方法，治疗干预这些现象。

DESCRIPTION (provided by applicant): Released endogenous opioid peptides regulate pain sensation, physiological stress responses and reward pathways. As such, endogenous opioids are believed to act as key modulators of the behavioral response to stress as well as drug self-administration. This proposal will assess the role of the endogenous kappa opioid system in the mediation of behavioral responses to stress and drug reward. In this proposal, we will perform a series of behavioral experiments exposing mice to the forced swim test, inducing a stress response mediated by the release of endogenous dynorphin peptides. Pilot results with C57BI/6 mice show that the mild stress induced by the forced swim test produced increases in immobility and tail-flick latency which were blocked by preadministration of the kappa opioid antagonist nor-BNl. Moreover, the increases in swimming immobility and tail-flick latency were observed in wild-type mice exposed to the forced swim stressor, but not in littermates lacking Dynorphin gene products. Future studies are planned to characterize the endogenous opioid peptides that are released in response to the swim stressor, as well as a parametric analysis to fully characterize the component of the stressor mediated by the endogenous kappa opioid system. In addition, these studies will be extended to examine the role of stress-induced endogenous kappa opioid activity in the response to rewarding drugs. Preliminary evidence shows that prior exposure of mice to a forced-swim stress induces a potentiation of the conditioned place-preference response to cocaine. In contrast, mice pretreated with nor-BNI or lacking dynorphin gene products prior to forced swimming did not show a stress-induced potentiation of cocaine conditioned place preference. Future studies with dynorphin wild type and knockout mice are planned wherein the duration of the stress effect and a parametric analysis of forced-swim stress impact on drug reward are examined by measuring the conditioned place preference for cocaine and heroin. In summary, it is expected that this data set would characterize a response to behavioral stress and drug reward regulated by the action of the endogenous kappa opioid system. A better understanding of the relationship between stress and endogenous kappa systems may lead to new insights into stress-induced relapse of drug abuse, as well as provide a new approach for therapeutic intervention in these phenomena.