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比例一直偏低。考虑到720万受影响的妇女 根据2018年的物质使用障碍(SUD)，这种缺乏研究导致缺乏有效的治疗 选择。最近，运动被强调为一种有希望的SUD和SSD的非药物治疗 女性可能会受到独特的影响，但这种现象的机制还没有完全了解。上一首 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(如可卡因)与月经期间雌二醇(E_2)的波动有关 周而复始。具体地说，在卵泡期使用药物后，女性报告了更大的欣快感、欲望和能量(即， 雌性大鼠处于较高的雌二醇期，而雌性大鼠雌激素受体的阻断减少了自我给药 可卡因。此外，雌激素充足的雌性啮齿类动物更活跃，而雌性啮齿类动物体内缺乏雌激素。 绝经后妇女和去卵巢(OVX)的啮齿动物会减少体力活动。一种潜力 机制解释是雌二醇对伏隔核多巴胺(DA)信号的影响 (NAC)，这是一个与奖励和成瘾相关的大脑区域。我之前的工作显示出很强的相关性 E_2缺乏雌性啮齿动物体力活动减少与6-丙酮酰四氢蝶呤合成酶的关系 (PTS)，NAC中DA合成的上游基因。这项建议旨在比较雌激素2丢失对 青少年(12-16周)对可卡因的自愿跑轮(VWR)和条件性位置偏爱(CPP) 野生型雌性C57BL6/J小鼠，行去卵巢手术。为了确定机制，我们提出了 通过立体定向向每组去势小鼠的NAC脑区注射E_2，以确定 VWR和CPP对可卡因的解救作用。我们将通过测量来检验潜在的机制 OVX和E_2处理及联合应用后NAC DA合成和受体表达的变化 这种变化会随着每一种行为而改变。 目的1将验证这样的假设，即OVX将降低年轻雌性小鼠的VWR，而直接微量注射 将E2注入南汽将挽救这一效应。我们将测试这种行为变化是否会因DA减少而发生 NAC的合成和受体的表达与Pts的减少有关。 目标2将验证这样的假设，即OVX将减少对可卡因的条件偏好，而直接 NAC内微量注射E_2可增强条件性偏爱。我们将测试这一行为是否 通过与目标1中测试的VWR类似的机制发生变化。 这项建议研究了雌二醇对雌性啮齿动物奖赏行为的影响，并将测试 其机制涉及NAC脑区DA的合成。此外，该项目将为申请者提供 有价值的培训，作为未来运动和成瘾研究职业生涯的基础。

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.