Investigation of how sex steroids and nicotinic acetylcholine receptors promote cocaine self-administration

研究性类固醇和烟碱乙酰胆碱受体如何促进可卡因自我给药

基本信息

批准号：
10625154
负责人：
Elizabeth Sneddon
金额：
$ 8.09万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625154
关键词：
Address Affect Alcohol consumption Alcohol dependence Alcohols Automobile Driving Brain region Calcium Cessation of life Chronic Clozapine Complex Consumption Darkness Data Dependence Diagnosis Ethanol Exhibits Exposure to Female Fiber Four Core Genotypes Future Genetic Glutamate Receptor Glutamates Goals Gonadal Hormones Gonadal Steroid Hormones Gonadal structure Home Human Image Indiana Individual Institution Intake Investigation Knowledge Knowledge acquisition Learning Ligands Literature Modeling Mus N-Methyl-D-Aspartate Receptors NMDA receptor antagonist Neuronal Plasticity Neurons Neurosciences Nicotinic Receptors Nose Nucleus Accumbens Oxides Pattern Phase Photometry Population Postdoctoral Fellow Pre-Clinical Model Publishing Quinine Rattus Research Research Personnel Research Project Grants Resistance Reverse Transcriptase Polymerase Chain Reaction Rewards Rodent Role Schedule Self Administration Sex Chromosomes Sex Differences System Techniques Testing Tissues Training United States Universities Viral Vector Vulnerable Populations Western Blotting Withdrawal Woman Work addiction addiction liability alcohol exposure alcohol misuse alcohol seeking behavior alcohol use disorder cocaine self-administration compulsion design designer receptors exclusively activated by designer drugs drinking drinking behavior drug abuse vulnerability experience experimental study high risk drinking innovation mRNA Expression male medical schools mouse model neural circuit neuromechanism optogenetics post-doctoral training pre-doctoral preclinical study programs protein expression receptor receptor expression sex skills tool vapor

项目摘要

PROJECT SUMMARY Alcohol use disorder (AUD) affects an estimated 16 million individuals, including about 5.1 million women. This number is on the rise as more women are increasing the amount of alcohol they drink, are partaking in more high-risk drinking behaviors, and are being diagnosed with AUD more often. Individuals with AUD exhibit compulsive alcohol drinking defined as excessive, uncontrolled alcohol intake and persistent use despite negative consequences. Because most preclinical studies have historically used only male subjects, current understanding of the neural mechanisms behind female vulnerability to AUD is limited. My published and preliminary studies demonstrate that females are more likely to drink and to respond for alcohol compulsively. In the proposed studies, I will investigate mechanisms underlying this vulnerability. Work in both humans and rodents suggests a role for the nucleus accumbens (NAc) core in driving compulsive-like alcohol intake in male subjects. Glutamate receptors in the NAc core are also implicated in compulsive-like alcohol intake in male subjects. Prior work on sex differences suggests that gonadal hormones may contribute to female vulnerability to drugs of abuse. Therefore, I am exploring the overarching hypothesis that female vulnerability to compulsive- like alcohol drinking is influenced by sex hormones and alcohol-induced increases in NAc core glutamate receptor expression. My proposed experiments (F99) will 1) show that activity in the NAc core contributes to female vulnerability to compulsively drink alcohol, 2) demonstrate that gonadal hormones influence heightened compulsive-like intake in females, but not males, and 3) determine whether gonadal hormones drive differential increases in NAc core glutamate receptor subunit mRNA and protein expression following exposure to chronic intermittent ethanol vapor. Overall, the proposed experiments will increase our knowledge about female alcohol addiction and will significantly impact the treatment of vulnerable populations such as women with AUD. My Sponsor, Dr. Anna Radke (Miami University), and Co-Sponsor, Dr. Frederic W. Hopf (Indiana University School of Medicine), are both experienced and highly regarded addiction neuroscientists known for their work studying compulsive-like alcohol drinking. The proposed Research and Training Plan will deepen my knowledge of the reward system, mechanisms underlying sex differences in addiction liability, and preclinical models of AUD. My training in chemogenetics, chronic intermittent ethanol vapor exposure, RT-PCR, and western blots will prepare me to learn more complex techniques, such as fiber photometry/ calcium imaging and optogenetics, as a postdoctoral researcher (K00). Collectively, this training will propel me toward my goal of establishing an independent research program focused on how sex differences in neuroplasticity, defined as changes in neuronal activity post-alcohol exposure, contribute to female vulnerability to alcohol addiction.

项目概要据估计，酒精使用障碍 (AUD) 影响着 1600 万人，其中包括约 510 万名女性。随着越来越多的女性饮酒量增加、饮酒量增加，这一数字还在上升。高风险饮酒行为，并且更频繁地被诊断为 AUD。持有澳元的个人展览强迫性饮酒的定义是过量、不受控制地摄入酒精并持续使用负面后果。由于大多数临床前研究历史上仅使用男性受试者，目前对女性易受 AUD 影响的神经机制的了解还很有限。我发表的和初步研究表明，女性更有可能饮酒并对酒精产生强迫性反应。在在拟议的研究中，我将调查此漏洞背后的机制。在人类和啮齿类动物表明伏隔核（NAc）核心在驱动男性强迫性酒精摄入中发挥作用科目。 NAc 核心中的谷氨酸受体也与男性强迫性饮酒有关科目。先前关于性别差异的研究表明，性腺激素可能会导致女性脆弱性滥用药物。因此，我正在探索一个总体假设，即女性容易遭受强迫症—— 就像饮酒受到性激素的影响以及酒精引起的 NAc 核心谷氨酸增加一样受体表达。我提出的实验 (F99) 将 1) 表明 NAc 核心的活动有助于女性容易强迫性饮酒，2) 证明性腺激素的影响增强女性强迫性摄入，但男性则不然，3）确定性腺激素是否驱动差异慢性暴露后 NAc 核心谷氨酸受体亚基 mRNA 和蛋白质表达增加间歇性乙醇蒸气。总的来说，拟议的实验将增加我们对女性酒精的了解成瘾，并将严重影响弱势群体（例如患有 AUD 的妇女）的治疗。我的赞助商 Anna Radke 博士（迈阿密大学）和共同赞助商 Frederic W. Hopf 博士（印第安纳大学学院）医学博士），都是经验丰富且备受推崇的成瘾神经科学家，以其研究工作而闻名强迫性饮酒。拟议的研究和培训计划将加深我对奖励制度、成瘾倾向性别差异背后的机制以及 AUD 的临床前模型。我的化学遗传学、慢性间歇性乙醇蒸气暴露、RT-PCR 和蛋白质印迹方面的培训将为您做好准备我学习更复杂的技术，例如纤维光度测定/钙成像和光遗传学，作为博士后研究员（K00）。总的来说，这次培训将推动我实现建立一个独立研究项目专注于神经可塑性的性别差异，定义为神经可塑性的变化酒精暴露后的神经元活动会导致女性容易酒精成瘾。