Estrogen receptor regulation of cocaine effects on dopamine terminals

项目摘要/摘要： 对于许多精神障碍，如物质使用障碍，性别是一个关键的生物变量，而女性 代表了一个特别脆弱的群体。对于可卡因使用障碍的女性来说，更快地过渡到成瘾， 服用更多的可卡因，经历更多的不良后果，保持戒烟的难度更大。 以前的研究已经揭示了中脑边缘多巴胺系统的显著性别差异，这是一种神经回路 在奖励学习和动机方面至关重要，并发现性腺激素17b-雌二醇是一种重要的 此漏洞的贡献者。起源于腹侧被盖的中脑边缘多巴胺系统 区域和纹状体的投射--已被证明参与了特定性别行为的表达 特别是在涉及可卡因奖励和动机的情况下。为了了解女性可卡因使用障碍，我们 需要了解药物反应的基本机制及其对药物反应的影响 这些药物作用的系统--我在这里主要关注多巴胺系统。虽然大量的工作集中在 男性和女性多巴胺神经元解剖和相对多巴胺水平的性别差异 纹状体轴突终末释放多巴胺的一个重要特征是它受到快速调制。 通过独立于躯体活动的地方调节机制。多巴胺系统含有高密度的 雌激素受体(ERA、ERB和GPER-1亚型)可能是重要的底物，通过 卵巢激素对多巴胺能功能有影响。事实上，存在强大的多巴胺系统。 卵巢激素对17β-雌二醇(E_2)增加多巴胺细胞活性和释放的调节 纹状体中的多巴胺终末。在目标1中，我将结合分析化学和光学成像技术 用药理学方法分离伏核核心中的多巴胺终末并表征其作用 雌激素受体亚型在调节突触前多巴胺释放中的作用。此外，以前的工作 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的选择性增加 发情期女性(具有高水平的循环E2)对多巴胺转运体的亲和力。在目标2中，我将定义 雌激素受体的直接操作如何影响多巴胺转运体介导的清除和活性 伏隔核核心末端的可卡因。这项工作建立在创新者在 研究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多巴胺转运蛋白上的可卡因效应。重要的是，这项工作 为我提供了绝佳的培训机会，同时为我提供了基本问题的答案 该领域的问题，在开发有效的可卡因使用障碍药物疗法方面势在必行。 总而言之，了解多巴胺调节的机制和药物对多巴胺的影响 系统对于我们理解支配两性神经传递的基本机制至关重要，因为 以及对以这一系统失调为特征的疾病的循证干预。

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.