Estrogen receptor regulation of cocaine effects on dopamine terminals

雌激素受体调节可卡因对多巴胺末端的影响

• 批准号: 10703405
• 负责人: Kirsty R. Erickson
• 金额: $ 3.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703405
• 关键词: Acute; Affect; Affinity; Agonist; Analytical Chemistry; Anatomy; Area; Behavior; Behavioral; Biological; Brain; Cells; Characteristics; Chemosensitization; Cocaine; Cocaine Dependence; Cocaine use disorder; Corpus striatum structure; Data; Disease; Dopamine; Drug usage; ESR1 gene; Estradiol; Estrogen Antagonists; Estrogen Receptors; Estrus; Evidence based intervention; Exhibits; Female; Foundations; GTP-Binding Proteins; Goals; Gonadal Hormones; Health; Imaging Techniques; Learning; Link; Measures; Mediating; Mediator; Mental disorders; Molecular; Monitor; Motivation; Mus; Neurobiology; Nucleus Accumbens; Optics; Ovarian hormone; Periodicity; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Predisposition; Presynaptic Terminals; Process; Receptor Activation; Regulation; Reporting; Research; Resolution; Rewards; Rodent; Role; Sampling; Scanning; Sex Differences; Signal Transduction; Slice; Social outcome; Stimulant; Substance Use Disorder; Surveys; System; Techniques; Ventral Tegmental Area; Vulnerable Populations; Woman; Work; addiction; adverse outcome; aged; behavioral outcome; cocaine reward; cocaine self-administration; conditioned place preference; density; direct application; dopamine system; dopamine transporter; dopaminergic neuron; drug action; experience; experimental study; illicit drug use; male; mesolimbic system; motivated behavior; neural circuit; neurotransmission; optical imaging; pharmacologic; presynaptic; proliferative phase Menstrual cycle; psychostimulant; receptor; response; sex; training opportunity; uptake

PROJECT SUMMARY/ABSTRACT: For many psychiatric disorders, such as substance use disorder, sex is a critical biological variable and women represent a particularly vulnerable population. For cocaine use disorder women transition to addiction faster, take more cocaine, experience more adverse consequences, and have more difficulty remaining abstinent. Previous research has exposed significant sex differences in the mesolimbic dopamine system, a neural circuit critical in reward learning and motivation, and identified the gonadal hormone 17b-estradiol as a significant contributor to this vulnerability. The mesolimbic dopamine system - which originates in the ventral tegmental area and projects to the striatum - has been shown to be involved in the expression of sex-specific behavior especially as it relates to cocaine reward and motivation. To understand cocaine use disorder in females we need to understand the fundamental mechanisms by which drug responses are mediated and how this influences the systems these drugs act on – I focus here on the dopamine system. While substantial work has focused on sex differences in the anatomy of dopamine neurons and relative dopamine levels between males and females, an important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms independent of somatic activity. The dopamine system contains a high density of estrogen receptors (ERa, ERb, and GPER-1 subtypes) that likely serve as important substrates through which ovarian hormones exert their influence on dopaminergic function. Indeed, there is robust dopamine system regulation by ovarian hormones where 17β-estradiol (E2) increases dopamine cell activity and release from dopamine terminals in the striatum. In Aim 1, I will combine analytical chemistry and optical imaging techniques with pharmacology to isolate dopamine terminals in the nucleus accumbens core and characterize the role of specific estrogen receptor subtypes in the modulation of presynaptic dopamine release. Further, previous work from our lab has shown selective increases in cocaine-evoked dopamine release, cocaine potency, and cocaine affinity for the dopamine transporter in estrus females (with high levels of circulating E2). In Aim 2, I will define how direct manipulation of estrogen receptors affects dopamine transporter-mediated clearance and potency of cocaine at terminals in the nucleus accumbens core. This work builds on the foundation set by innovators in the field to examine the role of estrogen receptors in presynaptic dopamine dynamics, and further proposes to investigate how these mechanisms modulate cocaine effects at the dopamine transporter. Importantly, this work provides me with an exceptional training opportunity while simultaneously providing answers to fundamental questions in the field, which are imperative in developing effective pharmacotherapies for cocaine use disorder. Together, understanding the mechanisms governing dopamine regulation and drug effects on the dopamine system is vital to our understanding of the basic mechanisms that govern neurotransmission in both sexes, as well as evidence-based interventions for diseases that are characterized by dysregulation of this system.

项目概要/摘要： 对于许多精神疾病，例如物质使用障碍，性别是一个关键的生物学变量，女性 对于可卡因使用障碍，女性会更快地陷入成瘾状态， 服用更多的可卡因，会经历更多的不良后果，并且更难以保持戒断。 先前的研究揭示了中脑边缘多巴胺系统（一种神经回路）的显着性别差异 对奖励学习和动机至关重要，并确定性腺激素 17b-雌二醇是一种重要的 中脑边缘多巴胺系统是造成这种脆弱性的原因之一，该系统起源于腹侧被盖。 纹状体的区域和项目 - 已被证明参与特定性别行为的表达 特别是因为它与可卡因奖励和动机有关，为了了解女性的可卡因使用障碍，我们 需要了解介导药物反应的基本机制及其如何影响 这些药物作用的系统——我在这里关注的是多巴胺系统，而大量的工作集中在这一点上。 多巴胺神经元解剖学的性别差异以及男性和女性之间的相对多巴胺水平， 纹状体轴突末端释放多巴胺的一个重要特征是它受到快速调节 通过独立于体细胞活动的局部调节机制，多巴胺系统包含高密度。 雌激素受体（ERa、ERb 和 GPER-1 亚型）可能作为重要的底物 卵巢激素对多巴胺能功能产生影响，确实存在强大的多巴胺系统。 卵巢激素的调节，其中 17β-雌二醇 (E2) 增加多巴胺细胞活性和释放 在目标 1 中，我将结合分析化学和光学成像技术。 通过药理学分离伏隔核核心中的多巴胺末端并表征其作用 调节突触前多巴胺释放的特定雌激素受体亚型进一步，先前的工作。 我们实验室的研究表明，可卡因引起的多巴胺释放、可卡因效力和可卡因选择性增加 在目标 2 中，我将定义发情雌性（具有高水平的循环 E2）对多巴胺转运蛋白的亲和力。 直接操纵雌激素受体如何影响多巴胺转运蛋白介导的清除和效力 这项工作建立在伏隔核核心终端的可卡因基础上。 领域检查雌激素受体在突触前多巴胺动力学中的作用，并进一步提出建议 研究这些机制如何调节可卡因对多巴胺转运蛋白的作用。 为我提供了一次特殊的培训机会，同时提供了基本问题的答案 该领域的问题对于开发可卡因使用障碍的有效药物疗法至关重要。 一起了解多巴胺调节的机制和药物对多巴胺的影响 系统对于我们理解控制两性神经传递的基本机制至关重要，因为 以及针对以该系统失调为特征的疾病的循证干预措施。