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.

项目摘要过量食用酒精每年造成9.8％的可预防死亡，而滥用酒精费用每年的医疗保健和经济支出为25亿美元。尽管滥用酒精的成本很高，但在过去的十年中，消费量大大增加。只有3个FDA批准减少饮酒的药物治疗，所有这些都在实现和维持戒酒方面效率低下强调需要对酗酒进行更有效的治疗。发展的主要障碍之一酗酒的更好治疗方法是酒精的众多细胞和分子机制报酬。最近的研究表明，酒精的奖励性能取决于其与奖励途径中的烟碱乙酰胆碱受体（NACHRS）。中脑奖励电路中的nachrs 刺激多巴胺（DA）释放，可介导酒精奖励。 α4亚基在酒精成瘾，因为针对该亚基的药物治疗会降低人类和动物模型。此外，α4基因敲除小鼠显示出降低的酒精消耗和DA释放，不要减少对NACHR药物的饮酒。 α4NACHR在几种细胞类型中发现在腹侧对盖区域（VTA）中，包括DA投影神经元和局部GABA神经元，可提供 DA神经元的抑制作用。最近的研究表明，VTA GABA神经元是关键的介体奖励行为，因为激活这些神经元会破坏蔗糖的消耗，并避免了这种情况。酒精增加了DA神经元的发射频率，从而影响酒精奖励行为。酒精也是调节VTA GABA神经元的活性，但是NACHR在此过程中的作用尚未研究。该领域的当前方法无法探测α4NACHR在单个细胞群中的作用，而 NACHR在抑制性GABA神经元上调节酒精奖励的机制仍然未知。为了解决知识的这一差距，我们制定了一种有条件的病毒基因输送策略在VTA GABA神经元内选择性地敲低α4亚基。该提议的目的是定义 α4NACHR亚基在VTA GABA神经元中饮酒和奖励中的作用。我们假设这一点 VTA GABA神经元中包含α4亚基的NACHR会通过抑制DA神经元兴奋。该项目的具体目的包括：1）确定α4的作用小鼠自愿饮酒中VTA GABA神经元中的NACHR亚基； 2）确定 DA神经元激活和主观奖励性能中VTA GABA神经元中的α4NACHR亚基酒精。该提案将提供有关α4NACHR亚基在调节酒精奖励。通过确定酒精奖励中重要的细胞类型和NACHR亚基，这项研究的结果将为临床前酒精的开发和完善提供宝贵的见解停止药物，因此有助于解决美国最大的公共卫生问题之一。