Accumbens shell mu-opioid signaling in alcohol self-administration and relapse

伏隔壳 mu-阿片类信号传导在酒精自我给药和复发中的作用

基本信息

批准号：
8522641
负责人：
Jocelyn M Richard
金额：
$ 4.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-16 至 2016-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8522641
关键词：
Affect Agonist Alcohol abuse Alcohol consumption Alcohol dependence Alcohols Animals Area Behavioral Behavioral Mechanisms Behavioral Model Brain Brain region Consumption Cues Direct Costs Endorphins Enkephalin, Ala(2)-MePhe(4)-Gly(5)-Extinction (Psychology)Facilities and Administrative Costs Food GABA-A Receptor Globus Pallidus Glutamates Hypothalamic structure Implant Individual Infusion procedures Lateral Lead Leucine Enkephalin Medial Mediating Microinjections Motivation Naloxone Narcotic Antagonists Nature Neurologic Neurons Nucleus Accumbens Opioid Opioid Receptor Pattern Pharmaceutical Preparations Prefrontal Cortex Process Production Property Psychological Tests Psychological reinforcement Rattus Recruitment Activity Relapse Research Rewards Rodent Role Satiation Self Administration Sensory Signal Transduction Societies Source Structure Sucrose System Taste Perception Techniques Testing Training Work alcohol craving alcohol reinforcement alcohol relapse alcohol reward alcohol seeking behavior alcohol use disorder craving endogenous opioids gamma-Aminobutyric Acid human subject in vivo learning extinction meetings mu opioid receptors neuromechanism neurotransmission optogenetics pleasure preference public health relevance relating to nervous system research study

项目摘要

DESCRIPTION (provided by applicant): A large body of evidence points to the importance of endogenous opioids in alcohol drinking and reinforcement (1). The medial shell of nucleus accumbens (NAc) has emerged as an important neural substrate for these effects and may mediate problem alcohol use (2-9). Importantly, infusion of the mu-opioid receptor agonist, DAMGO, into rodent NAc potentiates alcohol consumption (10), yet the behavioral and neurological mechanisms of this effect remain unknown. Medial NAc shell is a critical relay for prefrontal cortical influences on both hypothalamus and ventral pallidum, forming an "extinction circuit" which may co -opt mechanisms normally devoted to satiety, and modulation of this circuit may serve as a critical mechanism of opioid-induced alcohol consumption and relapse (11-12). Glutamatergic inputs from infralimbic cortex to medial NAc shell are posited to suppress drug and alcohol seeking following extinction and during reinstatement (13- 14), potentially via inhibitory projections from NAc to ventral pallidum and lateral hypothalamus (11, 15). The proposed experiments will systemically test the psychological and neural mechanisms of NAc DAMGO- induced alcohol consumption, and in particular the effects of NAc shell DAMGO on this extinction circuit. The experiments in Aim 1 of this proposal will test the specific effects o NAc shell DAMGO in alcohol self - administration and cue-induced relapse to alcohol seeking, to determine what aspects of alcohol reward are enhanced by NAc mu-opioid signaling (i.e. palatability, motivation, or reinforcement). It is critical to understand how NAc shell mu-opioid signaling affects top-down inputs from infralimbic cortex that may normally suppress alcohol seeking and relapse. Aim 2 of the research plan will test whether selective activation of infralimbic inputs to NAc can suppress alcohol consumption and relapse, and whether NAc shell DAMGO blocks these effects, during alcohol self-administration and relapse. It is also vital to understand how NAc mu-opioid induced changes in alcohol seeking are encoded in downstream structures of the extinction circuit, including ventral pallidum and lateral hypothalamus, which may encode different aspects of alcohol reward. The experiments in Aim 3 will test whether neural activity in lateral hypothalamus or ventral pallidum encodes alcohol seeking, consumption, or relapse to alcohol seeking, or enhancements in any of these processes following NAc shell DAMGO.