Endogenous enkephalins and reward mechanisms

项目摘要/摘要 在我们对成瘾所涉及的神经生物学过程的理解上存在着根本的差距 尤其是药物配对线索(条件性增强因子)所产生的增加吸毒的复杂变化。 并引发旧病复发。识别条件化增强剂改变行为的新机制 对于未来设计新的治疗方法以控制药物渴求和防止再次上瘾至关重要。 这项工作的长期目标是加深我们对行为和神经生物学机制的理解 调节作为条件性增强剂的药物配对刺激。此应用程序的目标是识别 内源性脑啡肽能系统在调节可卡因相关增强特性中的作用 刺激是可卡因成瘾的重要部分。脑啡肽与三角洲阿片类药物的高亲和力 在奖赏通路中高表达的受体(DOPR)和DOPR的激活可以改变 对药物配对的提示作出反应，但没有主要的强化作用。我们最重要的假设是 作用于伏隔核壳内阿片受体(DOPR)的脑啡肽(NAc-S)起重要作用 在调节条件性强化特性的行为和神经化学机制中的作用 可卡因配对线索。这项建议将条件强化的行为测量与IN相结合 体内微渗析和综合质谱分析，实时评价其作用 脑啡肽和DOPR在建立和维持可卡因相关线索的显著中的作用。通过 创新地使用行为和神经化学测量技术，这项提议将扩展到 选择性调节条件性强化的新机制的研究现状 可卡因的直接的、主要的强化作用。最终，这样的知识有可能开发出新的 预防复发的治疗方法。

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.