Mu receptors and ethanol/dopamine interactions

Mu 受体和乙醇/多巴胺相互作用

基本信息

批准号：
8858471
负责人：
RUEBEN A. GONZALES
金额：
$ 26.34万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-12 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8858471
关键词：
Alcohol consumption Alcoholism Behavior Behavioral Biological Models Brain Brain region Chronic Clinical Cues Data Development Dopamine Dose Drug usage Environment Ethanol Exposure to Family Grant Health Human Interneurons Intervention Investigation Lead Long-Evans Rats Maintenance Measures Mediating Medical Microelectrodes Modeling Monitor Naltrexone Narcotic Antagonists Neurotransmitters Nucleus Accumbens Opioid Peptide Opioid Receptor Patients Peptides Pharmacological Treatment Pharmacotherapy Phase Play Prevention Process Property Public Policy Rattus Regulation Relapse Role Self Administration Societies Solutions Source System Testing Therapeutic Effect Time Ventral Tegmental Area Water Work alcohol abuse therapy alcohol availability alcohol effect alcohol reinforcement base beta-funaltrexamine clinical effect disorder later incidence prevention dopaminergic neuron drinking drinking behavior gamma-Aminobutyric Acid in vivo mesolimbic system mu opioid receptors neurochemistry neurophysiology novel preclinical study problem drinker receptor reinforced behavior research study

项目摘要

DESCRIPTION (provided by applicant): The mechanisms that underlie the development and maintenance of ethanol self-administration are not fully understood, but the involvement of dopamine in the mesolimbic system has been hypothesized for some time. Many neurochemical systems are known to regulate the activity of the mesolimbic dopamine system, for example, the opioid peptides and their receptors. Naltrexone, a clinically effective drug used to reduce relapse in alcoholism, is a broad spectrum opioid receptor antagonist, but its mechanism is not known in detail. Mu opioid receptors are anatomically located in the ventral tegmental area (VTA) and are thought to control VTA dopamine neuron activity through the inhibition of GABA interneurons. However, the role of this mechanism in ethanol's regulation of dopamine release, and the role of particular opioid receptor subtypes has not been firmly established. Our preliminary studies show that mu opioid receptors are involved in the mechanism by which ethanol stimulates dopamine release in the shell of the nucleus accumbens in the Long-Evans rat. However, it is still unknown whether mu opioid receptors are involved in the stimulation of mesolimbic dopamine system before or during voluntary ethanol administration. We propose to determine the dose- dependent effects of naltrexone (non-selective opioid receptor antagonist) and beta-funaltrexamine (selective mu opioid receptor antagonist on accumbal dopamine during operant self-administration of ethanol (Aim 1). Finally, the mechanism of the stimulation of mesolimbic dopamine during operant self-administration may involve an increase in the firing rate of dopamine neurons in the ventral tegmental area, but this has not been measured in vivo. We propose to do this in Aim 2. Together, the proposed experiments will help elucidate the role of mu opioid receptors in the modulation of mesolimbic dopamine activity by ethanol in a behaviorally relevant context.

描述（由申请人提供）：尚不完全了解乙醇自我给药的开发和维持的机制，但多巴胺在中溶胶系统中的参与已被假设一段时间以来。已知许多神经化学系统都可以调节中唇多巴胺系统的活性，例如阿片类肽及其受体。纳曲酮是一种用于减少酒精中毒复发的临床有效药物，是一种广泛的阿片类药物受体拮抗剂，但其机制尚不清楚。 Mu阿片受体在解剖学上位于腹侧对盖区（VTA），被认为通过抑制GABA中间神经元来控制VTA多巴胺神经元活性。但是，这种机制在乙醇对多巴胺释放的调节以及特定阿片受体亚型的作用中的作用尚未牢固确定。我们的初步研究表明，MU阿片类受体参与了乙醇刺激longevans大鼠伏伏核壳中多巴胺释放的机制。然而，在自愿乙醇给药之前或期间，是否参与了中脱脂胺多巴胺系统的刺激是否涉及MU阿片类受体。我们建议确定纳拉曲酮（非选择性阿片类药物受体拮抗剂）和β-甲曲胺的剂量依赖性作用（选择性MU阿片类药物受体拮抗剂对乙醇操作自我加入过程中伏托胺对乙醇的旋转自我加热（AIM 1）。腹侧对接区域中多巴胺神经元的发射速率尚未在体内进行测量。