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.

项目摘要/摘要：可卡因使用障碍会影响近100万美国人，但目前尚无批准的治疗方法有效的治疗或防止复发。复发的主要贡献者是药物配对的提示，可以引起感觉渴望人类并导致寻求毒品。提示保持毒品寻求行为之后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增强作用。以前的工作表明，奖励电路中涉及多巴胺能和谷氨酸能系统，其他研究已经暗示了内源性阿片类药物系统，尤其是在伏隔核中的介导行为由可卡因生成提示引起的。具体而言，阻止阿片类药物受体激活减弱了寻求药物行为。同样，伏隔核中内源性阿片类肽的Enkephalin水平增加已经显示了一些主要的钢筋，并可能导致恢复毒品寻求药物。鲜为人知关于内源性阿片类药物在条件增强中的作用，或者促成阿片类的机制对这种复杂的行为。为了了解内源性阿片类药物系统在成瘾和特别是在可卡因生成的提示中，我将探索对提示和阿片类药物受体的脑反应激活调节这些效果。当前的建议得到了我们的初步研究的支持 Delta阿片受体（DOR）的增强作用的药物响应，表明增加在条件加固中。在这里，我将测试中心假设，即获得的提示条件加强特性会导致伏伏壳中的Enkephalin的增加，该外壳作用于驱动可卡因生产线索的操作者的动物。这项工作将1）衡量和增强Enkephalin 水平和2）在伏隔核中操纵阿片受体激活。对可卡因条件加固的严格测试。这项工作将使人们更好地理解并深入了解可卡因提示的条件加强特性背后的基本机制。该提议将在1）体内神经肽收集中提供必要的培训，2）内源性阿片类药物系统和3）成瘾研究中的严格行为实验。技能和培训该提案中描述的机会将使我成为一名成功从事毒品的专业科学家开发以识别神经系统疾病的新型疗法。