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Role of the kappa opioid receptor system in learning and substance use disorders

kappa阿片受体系统在学习和物质使用障碍中的作用

基本信息

批准号：
10750800
负责人：
Zahra Farahbakhsh
金额：
$ 3.3万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750800
关键词：
Abstinence Address Agonist Alcohol consumption Automobile Driving Behavior Behavioral Bilateral Cells Chronic Cues Data Data Set Dependence Development Dynorphins Elements Etiology Event Female Fiber Goals High Prevalence Intake Internal Ribosome Entry Site Investigation Learning Ligands Measurement Measures Mediating Modeling Mus Negative Reinforcements Neurobiology Neurosciences Nucleus Accumbens Operant Conditioning Opioid Antagonist Pattern Pharmaceutical Preparations Pharmacological Treatment Phenotype Photometry Play Positive Reinforcements Process Psychological reinforcement Public Health Receptor Signaling Research Resolution Rewards Role Signal Transduction Stimulus Stress Substance Use Disorder System Testing Time Training Up-Regulation Viral Vector adaptive learning addiction antagonist discrete time drug reward dysphoria experimental study in vivo in vivo optical imaging kappa opioid receptors learned behavior male motivated behavior negative affect non-drug norbinaltorphimine novel optogenetics pharmacologic predictive modeling prevent receptor function receptor sensitivity reinforcer response self-directed learning sensor substance use

项目摘要

Project Summary Despite their high prevalence, the underlying neurobiology of substance use disorders is still not understood, limiting effective pharmacological treatment options. Characterized by disruptions in learning processes, substance use disorders are thought to develop with the transition from being motivated by the positive reinforcing effects of the substance, to negative reinforcement where use occurs to avoid or alleviate an aversive state during abstinence. It is hypothesized that substance-induced upregulations in kappa opioid receptor (KOR) signaling play a causal role in the dysphoria that drives negative reinforcement. In support of this idea, KOR antagonists decrease drug intake in models of chronic use or dependence and the nucleus accumbens, a region critical to reinforcement learning and motivated behaviors, is one of the regions in which substance use has been shown to upregulate the KOR system. Despite this evidence of a causal role for KOR signaling in substance use disorders, this system’s function in adaptive reinforcement processes and the sufficiency of its upregulation in driving maladaptive learning remains unknown. Here, we aim to address these issues through direct investigation of the role of the KOR system in positive and negative reinforcement learning through pharmacological manipulation, sub-second measurement of in vivo dynorphin dynamics, and optogenetic activation of the KOR system. In aim 1, I will pair systemic antagonism of the KOR system with positive and negative reinforcement operant conditioning tasks to elucidate the role of KOR signaling in adaptive learning. In aim 2, I will conduct sub-second resolution, in vivo optical imaging of dynorphin release in the nucleus accumbens to uncover the role of endogenous KOR system activity in encoding information during reinforcement learning processes. Finally, in aim 3, I will optogenetically evoke accumbal dynorphin release to determine the sufficiency of augmentation of the KOR system in driving the maladaptive learning that underlies addiction. Through the completion of this proposal, I will receive well-rounded training in conducting independent research and contribute to the field of addiction neuroscience’s understanding of the mechanism by which the KOR system is involved in adaptive and maladaptive reinforcement learning processes.

项目总结