Role of nicotinic receptors in inhibitory GABA neurons on alcohol reward and behavior

抑制性 GABA 神经元烟碱受体对酒精奖赏和行为的作用

基本信息

批准号：
9886068
负责人：
Janna K Moen
金额：
$ 4.05万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2021-02-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886068
关键词：
Abstinence Acute Address Agonist Alcohol abuse Alcohol consumption Alcohol dependence Alcohols Americas Animal Model Behavior Behavioral Behavioral Mechanisms Biological Assay Brain Cells Chronic Complex Consumption Corpus striatum structure Cre driver Development Dopamine Drug Receptors Electrophysiology (science)FDA approved Frequencies Future Goals Heavy Drinking Human Individual Infusion procedures Ion Channel Knockout Mice Knowledge Measures Mediating Mediator of activation protein Messenger RNA Midbrain structure Modeling Molecular Mus Neurobiology Neurons Nicotinic Receptors Pathway interactions Pattern Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiology Population Process Property Public Health Research Rewards Rodent Role Slice Sucrose Techniques Testing Time Transgenic Organisms United States Ventral Tegmental Area alcohol abuse therapy alcohol behavior alcohol response alcohol reward base behavior influence binge drinking cell type clinically relevant conditioned place preference cost design dopaminergic neuron drinking drug of abuse effective therapy gamma-Aminobutyric Acid genetic manipulation health care economics human model insight interest knock-down neural circuit novel novel therapeutics pre-clinical preference preventable death reduced alcohol use response reward circuitry small hairpin RNA therapeutic development therapy design viral gene delivery young adult

项目摘要

PROJECT SUMMARY Excessive consumption of alcohol contributes to 9.8% of preventable deaths annually, and alcohol abuse costs $2.5 billion each year in healthcare and economic expenses. Despite the high costs of alcohol abuse, consumption has increased significantly over the past decade. There are only 3 FDA-approved pharmacotherapies to reduce alcohol use, all with low efficacy in achieving and maintaining abstinence, highlighting the need for more effective treatments for alcohol abuse. One of the major barriers to developing better treatments for alcohol abuse is the multitude of cellular and molecular mechanisms underlying alcohol reward. Recent studies indicate the rewarding properties of alcohol are dependent upon its interaction with nicotinic acetylcholine receptors (nAChRs) in reward pathways. nAChRs in the midbrain reward circuit stimulate dopamine (DA) release, which mediates alcohol reward. The α4 subunit is of particular interest in alcohol addiction, as pharmacotherapies targeting this subunit decrease alcohol consumption in human and animal models. Additionally, α4 knockout mice show reduced alcohol consumption and DA release, and do not reduce their alcohol consumption in response to nAChR drugs. α4 nAChRs are found within several cell types in the ventral tegmental area (VTA), including DA projection neurons and local GABA neurons, which provide inhibitory tone to DA neurons. Recent studies demonstrate that VTA GABA neurons are critical mediators of reward behaviors, as activating these neurons disrupts sucrose consumption and conditions a place aversion. Alcohol increases DA neuron firing frequency, which influences alcohol reward behavior. Alcohol also modulates the activity of VTA GABA neurons, but the role of nAChRs in this process has not been studied. Current approaches in the field cannot probe the role of α4 nAChRs in individual cell populations, and the mechanism through which nAChRs on inhibitory GABA neurons modulate alcohol reward remains unknown. To address this gap in knowledge, we have developed a conditional viral gene delivery strategy that initiates knockdown of the α4 subunit selectively within VTA GABA neurons. The goal of this proposal is to define the role of the α4 nAChR subunit in VTA GABA neurons in alcohol consumption and reward. We hypothesize that nAChRs containing the α4 subunit in VTA GABA neurons decreases alcohol reward and consumption through inhibition of DA neuron excitability. The specific aims of this project include: 1) determine the role of the α4 nAChR subunit in VTA GABA neurons in voluntary alcohol consumption in mice; and 2) determine the role of the α4 nAChR subunit in VTA GABA neurons in the DA neuron-activating and subjective rewarding properties of alcohol. This proposal will provide novel and important information about the role of the α4 nAChR subunit in modulating alcohol reward. By identifying important cell types and nAChR subunits in alcohol reward, the results of this study will provide valuable insight into the development and refinement of preclinical alcohol cessation drugs and thus help address one of the largest public health problems in America.

项目概要每年过量饮酒导致 9.8% 的可预防死亡，而酗酒造成的成本尽管酗酒的成本很高，但每年的医疗保健和经济支出仍高达 25 亿美元。过去十年消费量显着增加只有 3 个获得 FDA 批准。减少酒精使用的药物疗法，在实现和维持戒酒方面效果都很差，强调需要对酗酒进行更有效的治疗，这是发展的主要障碍之一。酒精滥用的更好治疗方法是酒精背后的多种细胞和分子机制最近的研究表明，酒精的奖励特性取决于它与酒精的相互作用。中脑奖赏回路中奖赏通路中的烟碱乙酰胆碱受体 (nAChR)。刺激多巴胺 (DA) 释放，调节酒精奖励，其中 α4 亚基特别受关注。酒精成瘾，因为针对该亚基的药物疗法可减少人类和酒精的摄入量此外，α4 基因敲除小鼠的饮酒量和 DA 释放量均有所减少，但事实并非如此。减少饮酒以应对 nAChR 药物 α4 nAChR 存在于多种细胞类型中。腹侧被盖区 (VTA)，包括 DA 投射神经元和局部 GABA 神经元，它们提供最近的研究表明，VTA GABA 神经元是 DA 神经元的抑制性调节因子。奖励行为，因为激活这些神经元会破坏蔗糖的消耗并导致地方厌恶。酒精会增加 DA 神经元的放电频率，从而影响酒精奖励行为。调节 VTA GABA 神经元的活性，但 nAChR 在此过程中的作用尚未研究。目前该领域的方法无法探测 α4 nAChR 在单个细胞群中的作用，并且抑制性 GABA 神经元上的 nAChR 调节酒精奖赏的机制仍不清楚。为了解决这一知识差距，我们开发了一种条件病毒基因传递策略，该策略启动选择性敲低 VTA GABA 神经元内的 α4 亚基该提案的目标是定义 VTA GABA 神经元中的 α4 nAChR 亚基在酒精消耗和奖励中的作用。 VTA GABA 神经元中含有 α4 亚基的 nAChR 通过以下方式降低酒精奖励和消耗：该项目的具体目标包括：1）确定α4的作用。 VTA GABA神经元中的nAChR亚基在小鼠自愿饮酒中的作用；2)确定 VTA GABA 神经元中的 α4 nAChR 亚基在 DA 神经元激活和主观奖励特性中的作用该提案将提供有关 α4 nAChR 亚基在酒精中的作用的新颖且重要的信息。通过识别酒精奖励中的重要细胞类型和 nAChR 亚基，调节酒精奖励。这项研究的结果将为临床前酒精的开发和完善提供有价值的见解戒烟药物，从而有助于解决美国最大的公共卫生问题之一。