Alcohol disrupts the balance between dopamine and GABA co-released by midbrain dopamine neurons

酒精破坏中脑多巴胺神经元共同释放的多巴胺和 GABA 之间的平衡

基本信息

批准号：
10172801
负责人：
Jun Ding
金额：
$ 36.11万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172801
关键词：
Acute Adult Advocate Affect Alcohol consumption Alcohol dependence Alcoholism Alcohols American Attenuated Basal Ganglia Behavioral Biochemical Biochemistry Blood alcohol level measurement Brain Cells Chronic Corpus striatum structure Data Development Diamines Disease Dopamine Dorsal Down-Regulation Drug Addiction Drug Metabolic Detoxication Drug abuse Drug usage Electrophysiology (science)Emetics Equilibrium Ethanol Genetic Glutamates Grant Health Heavy Drinking Home Human Image Impairment Incidence Injections Intake Knowledge Lasers Lead Learning Link Mediating Memory Metabolic Methodology Midbrain structure Mus Mutation Nausea Neurologic Neuronal Plasticity Neurons Neurotransmitters Oxidases Pathologic Pathway interactions Pharmacology Physiological Population Predisposition Presynaptic Terminals Property Psychotherapy Putrescine Resolution Risk Role Signal Transduction Social Problems Structure Synapses Synaptic Transmission Synaptic plasticity Testing Vesicle Virus Work addiction alcohol exposure alcohol prevention alcohol use disorder aldehyde dehydrogenase 1 aldehyde dehydrogenases attenuation base binge drinking cell type chronic alcohol ingestion combat dopaminergic neuron drinking drinking behavior drug of abuse experience experimental study gamma-Aminobutyric Acid neural circuit neuroadaptation neurotransmission neurotransmitter release new technology novel novel therapeutics optogenetics patch clamp postsynaptic preference prevent social therapeutic target tool transmission process two-photon vesicular monoamine transporter

项目摘要

Project Summary: Clear neuroadaptations occur as a result of alcohol use disorders, underlying the debilitating health risks and social problems associated with the disease. While changes in GABAergic, glutamatergic and dopaminergic neurotransmission are strongly implicated, the precise neurological mechanisms that cause enhanced susceptibility of alcohol intake and preference are not yet well understood. As a result, current treatments available to combat alcoholism are sparse and nonspecific— besides psychotherapy, detoxification and nausea-inducing, emetic drugs, there are no pharmacological targets for treating the disease. Recent studies have uncovered non-canonical GABA synthesis mediated by aldehyde dehydrogenase 1a1 (ALDH1a1) and co-release from dopaminergic midbrain neurons, and we have gathered strong evidence suggesting that this alternative GABA synthesis pathway is diminished with blood alcohol levels that are associated with binge drinking. Methodological advances now provide the opportunity to directly examine and dissect the role of this GABA pathway in acute and chronic alcohol exposure. In this proposal, we hypothesize that the balance between co-released dopamine and GABA by midbrain dopamine neurons is critical for postsynaptic striatal spiny projection neurons (SPNs). In addition, alcohol and/or its metabolic product inhibit dopaminergic GABA by impairing GABA non-canonical synthesis, ultimately perturbing the co-released GABA by dopamine neurons in the dorsal striatum, and lead to enhancement in susceptibility of alcohol intake and preference. We will employ the use of genetically modified mice and virus injections to directly examine dopamine neurons and the specific pathways involved in GABA synthesis, modulation and release. By optogenetic activation of dopamine terminals in the striatum and whole-cell patch clamp on identified principle striatal cells, our experiments will provide a high-resolution assessment of the function of dopaminergic GABAergic in normal and enhanced alcohol intake and preference conditions. Combined with imaging, electrophysiology, optogenetics, biochemistry and behavioral analysis, this proposal provides a unique, multi- faceted approach to study dopamine and GABA co-release in the basal ganglia, and the mechanisms by which chronic binge drinking alters this form of neurotransmitter release. Based on our compelling preliminary findings, we aim to 1) examine whether cell-type specific deletion of ALDH1a1 in dopamine neurons leads to enhanced alcohol preference; 2) pinpoint the mechanism underlying the inhibition of co-released GABA by alcohol; and 3) investigate alcohol modulation of functional interplay between GABA and dopamine in the striatum. Our novel initial findings and the studies proposed in this grant will close the gaps in our knowledge about GABA synthesis in dopaminergic neurons and create a new window into our understanding of synaptic mechanisms underlying enhanced alcohol intake and preference, providing better tools and earlier targets for the treatment or prevention of alcohol use disorders.

项目概要：酒精使用障碍会导致明显的神经适应，从而导致健康状况恶化与疾病相关的风险和社会问题。多巴胺能神经传递密切相关，导致的精确神经机制因此，目前对酒精摄入和偏好的敏感性增强尚不十分清楚。除了心理治疗、戒毒之外，可用于对抗酗酒的治疗方法很少且非特异性和引起恶心、催吐的药物，目前尚无治疗该疾病的药理学靶点。研究发现乙醛脱氢酶 1a1 介导的非经典 GABA 合成 (ALDH1a1) 和多巴胺能中脑神经元的共同释放，我们已经收集到了强有力的证据表明这种替代性 GABA 合成途径会随着血液中酒精浓度的降低而减弱方法学的进步现在提供了直接检查和饮酒的机会。剖析该 GABA 途径在急性和慢性酒精暴露中的作用。中脑多巴胺神经元共同释放的多巴胺和 GABA 之间的平衡对于此外，酒精和/或其代谢产物会抑制突触后纹状体棘投射神经元（SPN）。多巴胺能 GABA 通过损害 GABA 非规范合成，最终扰乱共同释放的 GABA 通过背侧纹状体的多巴胺神经元，导致酒精摄入和酒精敏感性增强我们将使用转基因小鼠和病毒注射来直接检查。多巴胺神经元以及参与 GABA 合成、调节和释放的特定途径。根据确定的原理光遗传学激活纹状体中的多巴胺末端和全细胞膜片钳纹状体细胞，我们的实验将对多巴胺能的功能提供高分辨率的评估正常和增强的酒精摄入量和偏好条件下的 GABAergic 结合成像，电生理学、光遗传学、生物化学和行为分析，该提案提供了独特的、多研究多巴胺和 GABA 在基底神经节中共同释放的多面方法及其机制长期酗酒会改变这种形式的神经递质释放。基于我们令人信服的初步发现，我们的目标是 1) 检查细胞类型特异性缺失是否多巴胺神经元中的 ALDH1a1 导致酒精偏好增强 2) 查明机制；酒精对共同释放的 GABA 的抑制作用；3) 研究酒精对功能的调节作用纹状体中 GABA 和多巴胺之间的相互作用。我们的初步发现和研究中提出的研究。这笔资助将缩小我们关于多巴胺能神经元 GABA 合成的知识空白，并创建一个我们了解增加酒精摄入量的突触机制的新窗口偏好，为治疗或预防酒精使用障碍提供更好的工具和更早的目标。