The Role of Estradiol on Central Dopamine Signaling and its Associations with Cocaine Preference and Exercise

摘要 从历史上看，女性在成瘾研究中的代表性不足。考虑到720万妇女受到影响 在2018年的物质使用障碍（SUD）中，缺乏研究导致缺乏有效的治疗方法。 选项.运动最近被强调为SUD的有希望的非药物治疗， 妇女可能受到独特的影响，但造成这一现象的机制尚不完全清楚。先前 对人类和啮齿动物模型的研究表明，体力活动和对 精神刺激药物（例如，可卡因）与整个月经期间雌二醇（E2）的波动相关 周期具体来说，女性报告在卵泡期间使用药物后有更大的欣快症、欲望和能量（即， 更高的E2）阶段的周期，而雌激素受体的阻断减少了雌性大鼠的自我管理 可卡因。此外，E2充足的雌性啮齿类动物更活跃，而E2的损失则会增加雌性啮齿类动物的体力活动。 绝经后妇女和卵巢切除（OVX）的啮齿动物减少体力活动。一个潜在 其机制解释是E2对丘脑核中多巴胺（DA）信号的影响 (NAc)这是一个与奖赏和成瘾有关的大脑区域。我之前的研究表明 雌鼠E2耗竭后体力活动减少与6-乙酰基四氢蝶呤合酶之间的关系 (Pts)，NAc中DA合成上游的基因。这项建议旨在比较E2损失对 年轻人（12-16周）对可卡因的自愿轮跑（VWR）和条件性位置偏好（CPP） 已经历OVX手术的野生型雌性C57 B16/J小鼠。为了确定机制，我们建议 将E2直接立体定位注射到每组OVX小鼠的NAc脑区，以确定 可卡因对VWR和CPP的拯救作用。我们将通过测量来研究潜在的机制。 OVX和E2治疗后NAc中DA合成和受体表达的变化及其相关性 每一种行为的变化。 目的1将验证OVX将降低年轻雌性小鼠VWR的假设，而直接显微注射 E2进入NAc将挽救这种效应。我们将测试这种行为变化是否发生在减少DA 合成和受体表达的NAc通过一个机制，涉及减少Pts。 目的2将检验OVX将减少可卡因的条件偏好，而直接 向NAc内微量注射E2可增加条件性偏爱。我们将测试这种行为 通过与目标1中测试的VWR类似的机制发生变化。 本研究旨在探讨雌鼠E2对奖励行为的影响，并将测试雌鼠是否会产生奖励行为。 该机制涉及NAc脑区中的DA合成。此外，该项目将为申请人提供 有价值的培训，作为未来运动和成瘾研究事业的基础。

Abstract Historically, women have been underrepresented in addiction research. Given the 7.2 million women affected by substance use disorder (SUD) in 2018, this lack of research contributes to a lack of effective treatment options. Exercise has recently been highlighted as a promising non-pharmacological treatment for SUD and women may be uniquely affected, but mechanisms for this phenomenon are not fully understood. Previous investigations in humans and rodent models have shown that both physical activity and preference for psychostimulant drugs (e.g., cocaine) correlate with fluctuations in estradiol (E2) throughout the menstrual cycle. Specifically, women report greater euphoria, desire, and energy after drug use during the follicular (i.e., higher E2) phase of their cycle, while blockade of estrogen receptors in female rats reduces self-administration of cocaine. In addition, E2-sufficient female rodents are more physically active, while loss of E2 in postmenopausal women and ovariectomized (OVX) rodents reduces physical activity. One potential mechanistic explanation for this is the effect of E2 on dopamine (DA) signaling in the nucleus accumbens (NAc), a brain region associated with reward and addiction. My previous work has shown a strong correlation between reduced physical activity in E2-depleted female rodents and 6-pyruvoyltetrahydropterin synthase (Pts), a gene upstream of DA synthesis in the NAc. This proposal seeks to compare the effect of E2 loss on voluntary wheel-running (VWR) and conditioned place preference (CPP) for cocaine in young (12-16 weeks) wild-type female C57Bl6/J mice that have undergone OVX operations. To determine mechanism, we propose to stereotaxically inject E2 directly into the NAc brain region of each group of OVX mice to determine the rescue effect on both VWR and CPP for cocaine. We will examine the potential mechanism by measuring changes in DA synthesis and receptor expression in the NAc following OVX and E2 treatment and associating such changes with each behavior. Aim 1 will test the hypothesis that OVX will reduce VWR in young female mice, while direct microinjection of E2 into the NAc will rescue this effect. We will test whether this behavioral change occurs by reduced DA synthesis and receptor expression in the NAc via a mechanism involving reduction in Pts. Aim 2 will test the hypothesis that OVX will reduce conditioned preference for cocaine, while direct microinjection of E2 into the NAc will increase conditioned preference. We will test whether this behavioral change occurs by a similar mechanism to VWR as tested in Aim 1. This proposal examines the effect of E2 on rewarding behaviors in female rodents and will test whether the mechanism involves DA synthesis in the NAc brain region. Furthermore, this project will provide the applicant valuable training, serving as a foundation for a future career in exercise and addiction research.