Estrogen receptor regulation of cocaine effects on dopamine terminals

项目总结/摘要： 对于许多精神疾病，如物质使用障碍，性别是一个关键的生物变量，妇女 是一个特别脆弱的群体。对于可卡因使用障碍的女性来说， 服用更多的可卡因，经历更多的不良后果，更难保持禁欲。 先前的研究已经揭示了中脑边缘多巴胺系统（一种神经回路）的显著性别差异 关键的奖励学习和动机，并确定了性腺激素17 b-雌二醇作为一个显着的 造成这种脆弱性。中边缘多巴胺系统-起源于腹侧被盖 区域和项目的纹状体-已被证明参与表达的性别特异性行为 尤其是与可卡因奖励和动机有关的。为了了解女性可卡因使用障碍， 需要了解药物反应介导的基本机制以及这如何影响 这些药物作用的系统--我这里关注的是多巴胺系统。虽然大量的工作集中在 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， 多巴胺从纹状体轴突末梢释放的一个重要特征是它被快速调节 通过独立于体细胞活动的局部调节机制。多巴胺系统含有高密度的 雌激素受体（ERa，ERb和GPER-1亚型）可能作为重要底物， 卵巢激素对多巴胺能功能有影响。事实上，有强大的多巴胺系统 卵巢激素的调节，其中17β-雌二醇（E2）增加多巴胺细胞的活性和释放， 纹状体的多巴胺末梢在目标1中，我将联合收割机分析化学和光学成像技术相结合 用药理学方法分离多巴胺末梢在脑桥核的核心，并表征作用， 特异性雌激素受体亚型调节突触前多巴胺释放。此外，以前的工作 我们实验室的研究表明，可卡因诱发的多巴胺释放，可卡因效力和可卡因 动情期雌性（循环E2水平高）中多巴胺转运蛋白的亲和力。在目标2中，我定义 雌激素受体的直接操作如何影响多巴胺转运蛋白介导的清除和效力， 可卡因在脑桥核核心的末端。这项工作建立在创新者在 领域，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可卡因对多巴胺转运蛋白的作用。重要的是，这项工作 为我提供了一个特殊的培训机会，同时提供了基本的答案， 这些问题在开发可卡因使用障碍的有效药物疗法方面至关重要。 总之，了解多巴胺调节机制和药物对多巴胺的影响， 系统是至关重要的，我们了解的基本机制，管理神经传递在两性， 以及针对以该系统失调为特征的疾病的循证干预措施。

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.