A novel role for midbrain glutamate co-transmitting neurons in alcohol drinking and motivated behaviors

中脑谷氨酸共传递神经元在饮酒和动机行为中的新作用

基本信息

批准号：
10307442
负责人：
ZACHARY FREYBERG
金额：
$ 20.11万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307442
关键词：
Adolescence Adolescent Adult Age Alcohol consumption Alcohol dependence Alcohols Attenuated Behavioral Cells Chemosensitization Consumption Corpus striatum structure Development Dopamine Dose Female Female Adolescents Fiber Future Glutamates Home Human Individual Kinetics Lead Life Measures Medial Mediator of activation protein Methods Midbrain structure Modeling Molecular Motivation Neurons Pathogenesis Pharmaceutical Preparations Photometry Play Population Property Rattus Reporting Rewards Risk Role Self Administration Sex Differences Site Societies Stimulus Tyrosine 3-Monooxygenase Ventral Tegmental Area Vesicle Work alcohol effect alcohol reinforcement alcohol response alcohol reward alcohol sensitivity alcohol use disorder base dopaminergic neuron drinking drinking behavior drug reward effective intervention family burden glutamatergic signaling in vivo insight knock-down male molecular imaging motivated behavior novel novel therapeutics pre-clinical sensor sex small hairpin RNA therapeutically effective tool transmission process underage drinking vesicular glutamate transporter 2

项目摘要

PROJECT SUMMARY Early adolescent alcohol use is one of the best predictors of risk for developing an alcohol use disorder (AUD) later in life. Generally, adolescents are more likely to report positive, rewarding effects of alcohol and fewer negative effects, which can lead to an increased propensity to consume larger volumes of alcohol. The molecular mechanisms underlying enhanced sensitivity to alcohol reward are poorly understood, but if identified, could lead to novel methods for reducing abuse liability and treating AUD in a manner that is uniquely tailored to adolescents and adults. Glutamate signaling is strongly implicated in the vulnerability to and pathogenesis of AUDs. Recent preclinical work has further refined this observation by showing that a population of neurons that express vesicular glutamate transporter 2 (VGLUT2) are strongly implicated in modulating drug reward. We have discovered that this distinct subpopulation of VGLUT2+ glutamatergic neurons is also dopaminergic. We also found glutamate potentiates activity-dependent vesicular dopamine loading and release. Thus, while glutamate and dopamine have both been individually implicated in the reinforcing effects of alcohol, glutamate and dopamine may also act synergistically to regulate sensitivity to alcohol. Notably, VGLUT2 expression is developmentally regulated, with expression peaking in adolescence and decreasing with age, which may explain why adolescents are particularly sensitive to the rewarding effects of alcohol. Additionally, we discovered strong sex differences in the expression of VGLUT2 including in glutamate/dopamine co-transmitting neurons, with females expressing more VGLUT2 relative to males. Thus, VGLUT2 expression may also explain why females are differentially sensitive to alcohol reward. Until recently, it has been difficult to functionally dissect subpopulations of glutamate neurons, including those that co-transmit dopamine, particularly in rats. However, we can now selectively control expression of a VGLUT2 in glutamate/dopamine neurons, and answer several key questions: 1) how does alcohol alter co-release of glutamate and dopamine from TH+/VGLUT2+ terminals in the mNAcSh?; 2) does manipulation of levels of VGLUT2 expression in mVTA glutamate/dopamine neurons modify alcohol reinforcement and motivation differentially in males and females and across key developmental stages (i.e., adolescence and adulthood)? Our central hypotheses are: i) Amount of glutamate/dopamine co- release will vary according to age and sex based on levels of VGLUT2 expression under basal conditions and in response to alcohol (Aim 1); ii) Manipulating levels of VGLUT2 expression will alter alcohol reinforcement and motivated behaviors (Aim 2). Using a combination of molecular, imaging, and behavioral tools, we will definitively identify the mechanistic role of subpopulations of midbrain glutamatergic neurons in alcohol reinforcement and motivation, and drive future development of new, more effective interventions for alcohol use disorder.

项目摘要早期的青春期饮酒是发展饮酒障碍风险的最佳预测因素之一（AUD）后来生活。通常，青少年更有可能报告酒精的积极，有益的影响，更少负面影响，这可能导致倾向增加，以消耗大量的酒精。分子对饮酒奖励的敏感性增强的机制知之甚少，但如果确定，可以领导以减少滥用责任和以独特量身定制的青少年的方式处理AUD的新方法和成人。谷氨酸信号传导与AUD的脆弱性和发病机理非常重要。最近的临床前工作通过表明表达的神经元的群体进一步完善了这一观察结果囊泡谷氨酸转运蛋白2（VGLUT2）与调节药物奖励有着强烈的影响。我们有发现VGLUT2+谷氨酸能神经元的这种独特的亚群也是多巴胺能。我们也是发现谷氨酸增强了活性依赖性囊泡多巴胺的负载和释放。因此，谷氨酸多巴胺都与酒精，谷氨酸和多巴胺也可以协同作用以调节对酒精的敏感性。值得注意的是，vglut2的表达是在发育中受调节，表达在青春期达到峰值，并且随着年龄的增长而下降，这可以解释为什么青少年对酒精的奖励作用特别敏感。此外，我们发现了强壮 vglut2表达的性别差异，包括谷氨酸/多巴胺共同传播神经元，与相对于男性，女性表达更多的vglut2。因此，vglut2表达也可以解释为什么女性对酒精奖励有差异敏感。直到最近，很难在功能上进行剖析谷氨酸神经元的亚群，包括那些共同特许多巴胺，尤其是在大鼠中。然而，现在，我们可以选择性地控制谷氨酸/多巴胺神经元中vglut2的表达，并回答几个关键问题：1）酒精如何改变TH+/VGLUT2+终端的谷氨酸和多巴胺的共释放在mnacsh？ 2）是否操纵MVTA谷氨酸/多巴胺神经元中VGLUT2表达水平在男性和女性以及关键发展的差异上修改酒精加强和动机阶段（即青春期和成年）？我们的中心假设是：i）谷氨酸/多巴胺共同数量根据基础条件下的vglut2表达水平，释放会因年龄和性别而变化响应酒精（AIM 1）； ii）操纵vglut2表达水平将改变酒精加强和动机行为（目标2）。结合分子，成像和行为工具，我们将确定确定中脑谷氨酸能神经元在酒精加强和动机，并推动对饮酒障碍的新的，更有效的干预措施的未来发展。