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

项目总结 据估计，酒精使用障碍(AUD)影响了1600万人，其中包括约510万女性。 这一数字正在上升，因为越来越多的女性增加了饮酒量，参与了更多的 高危饮酒行为，并被诊断为AUD的频率越来越高。AUD个人展品 强迫性饮酒定义为过度、无节制的饮酒和持续饮酒，尽管 负面后果。因为大多数临床前研究历来只使用男性受试者，目前 对女性易患AUD背后的神经机制的了解有限。我出版的和 初步研究表明，女性更有可能饮酒，并对酒精做出强迫性反应。在……里面 在拟议的研究中，我将调查这一漏洞背后的机制。在人类和 啮齿动物提示伏隔核(NAC)核心在驱动雄性强迫性饮酒中的作用 研究对象。NAC核心中的谷氨酸受体也与男性强迫性饮酒有关 研究对象。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。 向滥用毒品致敬。因此，我正在探索一个重要的假设，即女性对强迫症的易感性- 和酒精一样，饮酒也受到性激素和酒精诱导的NAC核心谷氨酸增加的影响 受体表达。我提议的实验(F99)将1)表明NAC核心中的活动有助于 女性对强迫性饮酒的易感性，2)表明性腺激素影响增强 女性的强迫性摄入，而不是男性，以及3)决定性腺激素是否驱动差异 慢性暴露对NAC核心谷氨酸受体亚单位基因和蛋白表达的影响 间歇性的乙醇蒸气。总体而言，拟议的实验将增加我们对女性酒精的了解 这将严重影响诸如澳元妇女等弱势群体的治疗。我的 赞助人安娜·拉德克博士(迈阿密大学)和共同赞助人弗雷德里克·W·霍普夫博士(印第安纳大学学院 都是经验丰富且备受推崇的成瘾神经学家，以他们的工作研究而闻名 像酗酒一样的强迫性饮酒。拟议的研究和培训计划将加深我对 奖赏系统，成瘾倾向的性别差异的机制，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和免疫印迹方面的培训将做好准备 我想学习更复杂的技术，如纤维光度学/钙成像和光遗传学，作为 博士后研究员(K00)。总体而言，这次培训将推动我朝着建立一个 独立研究项目的重点是性别在神经可塑性方面的差异，定义为 酒精暴露后的神经元活动，增加了女性对酒精成瘾的易感性。

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.