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

• 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
• 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

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）影响着约1600万人，其中包括约510万妇女。 随着越来越多的女性增加饮酒量， 高风险饮酒行为，并更频繁地被诊断为AUD。个人AUD展览 强迫性饮酒定义为过量，不受控制的酒精摄入和持续使用，尽管 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，因此目前 对女性对AUD易感性背后的神经机制的理解是有限的。我的出版和 初步研究表明，女性更有可能喝酒，并对酒精产生强迫性反应。在 在拟议的研究中，我将调查这种脆弱性的机制。在人类和 啮齿类动物表明，在驱动男性强迫性酒精摄入中，中脑核（NAc）核心发挥作用 科目NAc核心中的谷氨酸受体也与男性强迫性酒精摄入有关 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的脆弱性 滥用药物。因此，我正在探索一个总体假设，即女性对强迫性行为的脆弱性- 就像饮酒受到性激素和酒精诱导的核心谷氨酸盐增加的影响一样， 受体表达我提出的实验（F99）将表明：1）NAc核心的活动有助于 女性易受强迫性饮酒的影响，2）表明性腺激素的影响加剧 女性强迫性摄入，而不是男性，和3）确定性腺激素是否驱动差异 慢性暴露后NAc核心谷氨酸受体亚单位mRNA和蛋白表达增加 间歇性乙醇蒸汽。总的来说，拟议中的实验将增加我们对女性酒精的了解。 成瘾，并将显着影响治疗的弱势群体，如妇女与澳元。我 申办者，安娜Radke博士（迈阿密大学）和共同申办者，Frederic W.霍普夫（印第安纳州大学学院 他们都是经验丰富、备受推崇的成瘾神经科学家，以研究 强迫性饮酒拟议的研究和培训计划将加深我对 奖励系统，成瘾倾向性别差异的机制，以及AUD的临床前模型。我 将准备化学遗传学、慢性间歇性乙醇蒸气暴露、RT-PCR和蛋白质印迹方面的培训 我学习更复杂的技术，如纤维光度学/钙成像和光遗传学，作为一个 博士后研究员（K 00）。总的来说，这次培训将推动我朝着建立一个 一个独立的研究项目专注于神经可塑性的性别差异， 酒精暴露后的神经元活动，有助于女性对酒精成瘾的脆弱性。