Endogenous enkephalins and reward mechanisms

内源性脑啡肽和奖励机制

基本信息

批准号：
10203896
负责人：
EMILY M JUTKIEWICZ
金额：
$ 30.67万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203896
关键词：
Acetylcholine Address Affect Affinity American Behavior Behavioral Behavioral Mechanisms Binding Brain Chronic Chronic Disease Cocaine Cocaine Dependence Complex Corpus striatum structure Cues Data Development Dopamine Drug Addiction Drug Controls Enkephalins Female Future Glutamates Goals Health Knowledge Lead Learning Life Ligands Mass Spectrum Analysis Measurement Mediating Mediator of activation protein Microdialysis Mission Motivation Neurobiology Neurotransmitters Nucleus Accumbens Opioid Pathway interactions Pharmaceutical Preparations Pharmacology Play Procedures Process Property Psychological reinforcement Receptor Activation Receptor Signaling Relapse Reporting Research Rewards Role Sampling Sex Differences Site Societies Stimulus System Techniques Time United States National Institutes of Health Wood material Work addiction base behavior measurement delta opioid receptor design drug craving drug development drug of abuse drug relapse endogenous opioids experimental study in vivo innovation knock-down male neural circuit neurobiological mechanism neurochemistry novel paired stimuli pleasure prevent reinforcer response small hairpin RNA

项目摘要

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.

项目概要/摘要我们对成瘾所涉及的神经生物学过程的理解存在根本性的差距，特别是由增加吸毒的药物配对线索（条件强化物）产生的复杂变化行为并引发复发。识别条件强化物改变行为的新机制对于未来设计新疗法来控制毒瘾和防止毒瘾复发至关重要。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强化物的药物配对刺激。该应用程序的目的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组成部分。脑啡肽与 δ-阿片类药物具有高亲和力受体（DOPR），在奖赏途径中高度表达，DOPR 激活可以改变对药物配对的线索做出反应，而没有主要的强化作用。我们的总体假设是作用于伏隔核壳 (NAc-S) 中 δ-阿片受体 (DOPR) 的脑啡肽发挥着重要作用在介导条件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。该提案将把条件强化的行为测量与in 体内微透析和综合质谱分析实时评估脑啡肽和 DOPR 建立和维持可卡因相关线索的显着性。通过行为和神经化学测量技术的创新使用，该提案将扩展到现状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、主要的强化作用。最终，这些知识有可能开发出新的知识预防复发的治疗。