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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要：对于许多精神疾病，例如药物使用障碍，性是一种关键的生物学变量，女性代表一个特别脆弱的人群。对于可卡因疾病，妇女过渡到成瘾的速度更快，采取更多可卡因，经历更多的不利后果，并避免更加困难。先前的研究已经暴露了中唇多巴胺系统的显着性别差异，神经回路对奖励学习和动力至关重要，并确定性腺荷马犬17b-雌二醇是重要的造成这种脆弱性的贡献者。中唇多巴胺系统 - 起源于腹侧段纹状体的区域和项目 - 已显示与性别特定行为的表达有关特别是与可卡因的奖励和动力有关。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，以及这如何影响这些药物的系统作用 - 我在这里集中在多巴胺系统上。虽然大量工作重点是多巴胺神经元解剖学的性别差异和男性和女性之间的相对多巴胺水平，纹状体中轴突终端释放多巴胺的重要特征是它是快速调节的通过局部调节机制，独立于躯体活动。多巴胺系统含有高密度雌激素受体（ERA，ERB和GPER-1亚型）可能是重要的底物卵巢马对多巴胺能功能产生影响。确实，有强大的多巴胺系统通过卵巢激素调节，其中17β-雌二醇（E2）增加了多巴胺细胞的活性并从纹状体中的多巴胺末端。在AIM 1中，我将结合分析化学和光学成像技术用药理学分离伏隔核中多巴胺末端的药理学，并表征突触前多巴胺释放的调节中的特定雌激素受体亚型。此外，以前的工作从我们的实验室中，可卡因诱发的多巴胺释放，可卡因效力和可卡因的选择性增加对女性的多巴胺转运蛋白的亲和力（具有高水平的E2循环）。在AIM 2中，我将定义雌激素受体的直接操纵如何影响多巴胺转运蛋白介导的清除和效力可卡因在伏隔核中的末端。这项工作建立在创新者中的基础上野外检查雌激素受体在突触前多巴胺动力学中的作用，并进一步提出研究这些机制如何调节可卡因对多巴胺转运蛋白的影响。重要的是，这项工作为我提供出色的培训机会，同时为基本的答案提供答案该领域的问题，这对于开发可卡因使用障碍有效的药物治疗至关重要。共同了解管理多巴胺调节和药物对多巴胺的作用的机制系统对于我们对控制两性神经传递的基本机制的理解至关重要以及基于证据的疾病干预措施，这些疾病的特征是该系统的失调。