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.

描述（由申请人提供）：大量证据表明，内源性阿片类药物在饮酒和加固中的重要性（1）。伏隔核（NAC）的内侧壳已成为这些作用的重要神经底物，并可能介导问题酒精的使用（2-9）。重要的是，将Mu-阿片受体激动剂Damgo输注到啮齿动物NAC中增强了酒精消耗（10），但这种效应的行为和神经系统机制仍然未知。内侧NAC壳是对下丘脑和腹侧胸膜前额叶皮质影响的关键继电器，形成了一种“灭绝电路”，该电路可能会构成通常专用于饱腹感的机制，并且该电路的调节可能是阿片类药物诱发的酒精消耗和复发的关键机制（11-12）。从灌木丛皮质到内侧NAC壳的谷氨酸能输入被抑制在灭绝后和恢复期间（13-14）的吸毒和酒精，这可能是通过从NAC到NAC到腹侧粒子到腹侧的抑制性投射和侧面下丘脑（11，15）。提出的实验将系统地测试NAC DAMGO诱导的饮酒的心理和神经机制，尤其是NAC Shell Damgo对此灭绝电路的影响。该提案的目标1中的实验将测试nac壳damgo在酒精自我施用和提示引起的寻求酒精的复发中的特定效果，以确定NAC MU-Apopio-Apioid信号（即可服装，动机或增强型）增强酒精奖励的哪些方面。重要的是要了解NAC壳静脉静脉静脉 - 阿片类药物信号如何影响通常会抑制酒精寻求和复发的输液皮层的自上而下的输入。研究计划的AIM 2将测试在饮酒自我给药和复发期间，选择性激活Infralimbic输入到NAC是否可以抑制酒精消耗和复发，以及NAC Shell Damgo是否会阻止这些影响。了解如何在灭绝电路的下游结构中编码NAC MU-阿片类药物诱导的诱导的变化，包括腹侧粒子和下丘脑，这可能编码酒精奖励的不同方面。 AIM 3中的实验将测试下丘脑外侧或腹侧苍白球中的神经活动是否编码酒精寻求，消费或重新饮酒，或者在NAC Shell Damgo之后的任何这些过程中的任何一项增强。