Endogenous enkephalins and reward mechanisms

项目总结/摘要 我们对成瘾的神经生物学过程的理解存在根本性的差距， 特别是药物配对线索（条件反射）产生的复杂变化， 行为并引发复发。确定条件反射改变行为的新机制 对于未来设计新的治疗方法来控制药物渴望和防止成瘾复发至关重要。 这项工作的长期目标是进一步了解行为和神经生物学机制 介导作为条件反射剂的药物配对刺激。本申请的目的是确定 内源性脑啡肽能系统在调节可卡因相关的增强特性中的作用 这些刺激是可卡因成瘾的重要组成部分。脑啡肽以高亲和力与δ-阿片样物质结合 受体（DOPR），这是高度表达的奖励途径，和DOPR激活可以改变 对药物配对线索的反应，而没有主要的强化作用。我们的首要假设是 脑啡肽作用于延髓核壳（NAc-S）中的δ阿片受体（DOPR）， 在行为和神经化学机制中的作用， 可卡因配对线索这项建议将耦合行为测量条件强化与在 体内微透析和综合质谱分析，以实时评估 脑啡肽和DOPR在建立和维持可卡因相关线索的显著性方面的作用。通过 行为和神经化学测量技术的创新使用，这一建议将扩大超越 研究选择性介导条件强化的新机制，但不一定 可卡因的直接的、主要的强化作用。最终，这些知识有可能开发新的 预防复发的治疗。

Project Summary/Abstract There are fundamental gaps in our understanding of the neurobiological processes involved in addiction, in particular the complex changes produced by drug-paired cues (conditioned reinforcers) that increase drug-taking behavior and provoke relapse. Identifying novel mechanisms by which conditioned reinforcers modify behavior is essential for future efforts to design new treatments to control drug craving and prevent relapse to addiction. The long-term goal of this work is to further our understanding of the behavioral and neurobiological mechanisms mediating drug-paired stimuli that serve as conditioned reinforcers. The objective of this application is to identify the role of the endogenous enkephalinergic system in regulating the reinforcing properties of cocaine-associated stimuli that are an essential part of cocaine addiction. Enkephalins binds with high affinity to delta-opioid receptors (DOPRs), which are highly expressed within the reward pathway, and DOPR activation can alter responding for drug-paired cues without primary reinforcing effects. Our overarching hypothesis is that enkephalins acting at delta-opioid receptors (DOPRs) in the nucleus accumbens shell (NAc-S) play an essential role in the behavioral and neurochemical mechanisms mediating the conditioned reinforcing properties of cocaine-paired cues. This proposal will couple behavioral measurements of conditioned reinforcement with in vivo microdialysis and comprehensive mass spectrometry analysis to evaluate in real-time the role of the enkephalin and DOPRs in establishing and maintaining the salience of cocaine-associated cues. Through the innovative use of behavioral and neurochemical measurement techniques, this proposal will expand beyond the status quo to investigate novel mechanisms selectively mediating conditioned reinforcement but not necessarily the direct, primary reinforcing effects of cocaine. Ultimately, such knowledge has the potential to develop new treatments for preventing relapse.