Opioidergic mechanisms underlying cocaine conditioned reinforcement

可卡因条件强化背后的阿片样物质机制

基本信息

批准号：
10683069
负责人：
Lauren Grace Rysztak
金额：
$ 3.98万
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：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10683069
关键词：
Affect Affinity American Association Learning Attenuated Behavior Behavioral Binding Brain Cocaine Cocaine Abuse Cocaine use disorder Collection Complex Cues Data Dopamine Enkephalin Receptors Enkephalins Exposure to Extinction Feeling Female Glutamates Human Knowledge Lead Measures Mediating Microdialysis Neurobiology Neuropeptides Nucleus Accumbens Opioid Opioid Antagonist Opioid Peptide Opioid Receptor Pathway interactions Peptide Receptor Pharmaceutical Preparations Phase Procedures Property Psychological reinforcement Rattus Receptor Activation Relapse Reporting Research Rewards Role Scientist Sex Differences Stimulus Substance Use Disorder System Testing Training Work addiction antagonist behavioral response cocaine cue cocaine relapse cocaine seeking conditioning craving delta opioid receptor drug development drug of abuse drug relapse drug seeking behavior effective therapy endogenous opioids experimental study in vivo insight male naltrindole nervous system disorder neural neurobiological mechanism neurochemistry novel novel therapeutics paired stimuli pharmacologic reinforcer relapse prevention relapse risk response reward circuitry skills therapeutic target therapeutically effective training opportunity

项目摘要

Project summary/abstract: Cocaine use disorder affects nearly one million Americans, yet there are no current approved therapeutics for effective treatment or to prevent relapse. Major contributors to relapse are drug paired cues that can elicit feelings of craving in humans and lead to drug seeking. The ability of cues to maintain drug seeking behavior after sufficient number of cue and cocaine pairings is termed the conditioned reinforcing effects of cocaine. Previous work suggests that dopaminergic and glutamatergic systems in reward circuitry are involved, and other studies have implicated the endogenous opioid system, particularly in the nucleus accumbens, in mediating behavior elicited by cocaine-paired cues. Specifically, blocking opioid receptor activation attenuates drug seeking behavior. Similarly, increases in levels of enkephalin, an endogenous opioid peptide, in the nucleus accumbens have been shown with some primary reinforcers and can lead to reinstatement of drug seeking. Little is known about the role of endogenous opioids in conditioned reinforcement nor the opioidergic mechanisms contributing to this complex behavior. To gain insights into the contribution of the endogenous opioid system in addiction and specifically in cocaine-paired cues, I will explore the enkephalinergic response to cues and opioid receptor activation modulating these effects. The current proposal is supported by our preliminary studies that activation of the delta opioid receptor (DOR) potentiates operant responding for drug-paired cues, indicating an increase in conditioned reinforcement. Here I will test the central hypothesis that presentation of cues that have acquired conditioned reinforcing properties lead to an increase of enkephalin in the nucleus accumbens shell that acts on DORs to drive operant responding for cocaine-paired cues. This work will 1) measure and potentiate enkephalin levels and 2) manipulate opioid receptor activation pharmacologically in the nucleus accumbens during a stringent test of cocaine conditioned reinforcement. This work will lead to better understanding of and insight into the underlying mechanisms behind the conditioned reinforcing properties of cocaine cues. This proposal will provide me essential training in 1) in vivo neuropeptide collection, 2) pharmacological manipulation of the endogenous opioid system, and 3) rigorous behavioral experiments in addiction research. The skills and training opportunities described in this proposal will enable me to be a successful professional scientist working in drug development to identify novel therapeutics for neurological disorders.

项目概要/摘要：可卡因使用障碍影响着近百万美国人，但目前尚无批准的治疗方法有效治疗或预防复发。复发的主要因素是可以引起感觉的药物配对线索人类的渴望并导致寻求毒品。线索维持药物寻求行为的能力足够数量的提示和可卡因配对被称为可卡因的条件强化效应。以前的研究表明奖赏回路中的多巴胺能和谷氨酸能系统参与其中，其他研究也表明暗示内源性阿片类系统，特别是伏隔核中的内源性阿片类系统，与介导行为有关由可卡因配对线索引起。具体来说，阻断阿片受体激活会减弱药物寻求行为。同样，伏隔核中脑啡肽（一种内源性阿片肽）水平增加已被证明具有一些主要的强化物，并且可以导致恢复药物寻求。鲜为人知关于内源性阿片类药物在条件强化中的作用以及阿片类药物机制的贡献对于这种复杂的行为。深入了解内源性阿片类药物系统在成瘾和成瘾中的贡献特别是在可卡因配对线索中，我将探索对线索和阿片受体的脑啡肽能反应激活调节这些效应。目前的提议得到了我们的初步研究的支持，即激活 δ阿片受体（DOR）的增加增强了对药物配对线索的操作反应，表明增加在条件强化中。在这里我将测试中心假设，即呈现已获得的线索条件强化特性导致伏隔核壳中脑啡肽的增加，作用于 DOR 驱动操作者对可卡因配对线索做出反应。这项工作将 1) 测量和增强脑啡肽水平和2）在药理学上操纵伏隔核中的阿片受体激活可卡因条件强化的严格测试。这项工作将有助于更好地理解和洞察可卡因线索的条件强化特性背后的潜在机制。该提案将为我提供以下方面的基本培训：1) 体内神经肽收集，2) 药物操作内源性阿片类药物系统，3）成瘾研究中严格的行为实验。技能和培训本提案中描述的机会将使我成为一名成功的药物专业科学家开发以确定神经系统疾病的新疗法。