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.

项目摘要酒精使用障碍（AUD）影响约1600万人，其中包括约510万妇女。随着越来越多的女性在增加喝酒的数量，更多的人正在加入更多高风险的饮酒行为，并被更频繁地被诊断出患有AUD。有澳元展览的人强迫性饮酒定义为过度，不受控制的酒精摄入和持续使用负面后果。由于大多数临床前研究历史上仅使用男性受试者，所以了解女性脆弱性AUD背后的神经机制是有限的。我的出版和初步研究表明，女性更有可能喝酒和强迫性酒精反应。在拟议的研究，我将研究这种脆弱性的基础机制。在人类和啮齿动物表明伏隔核（NAC）核心在驱动男性的强迫性酒精摄入量中起作用主题。 NAC核中的谷氨酸受体也与男性的强迫性酒精摄入有关主题。性别差异的先前工作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，即女性易受强迫性的脆弱性像饮酒受到性激素的影响，NAC核心谷氨酸的酒精引起的增加受体表达。我提出的实验（F99）将表明NAC核心中的活动有助于女性强迫喝酒的脆弱性，2）证明性腺激素的影响增强了女性的强迫性摄入量，但不是男性，3）确定性腺激素是否驱动差异暴露于慢性间歇性乙醇蒸气。总体而言，拟议的实验将增加我们对女性酒精的了解成瘾，将极大地影响对弱势群体的治疗，例如aud女性。我的赞助商，安娜·拉德克（Anna Radke）博士（迈阿密大学）和共同赞助商弗雷德里克·W·霍普夫（Frederic W. Hopf）（印第安纳大学学校医学）是经验丰富且备受推崇的成瘾神经科学家以其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系统，成瘾责任中性别差异的基础机制以及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Western印迹的培训将准备我学习更多复杂的技术，例如光纤光度法/钙成像和光遗传学，博士后研究员（K00）。总的来说，这项培训将推动我建立一个目标独立研究计划的重点是神经可塑性的性别差异如何定义为变化酒精后暴露后神经元活动导致女性对酒精成瘾的脆弱性。