The role of GPER-1 and addiction

项目摘要/摘要 上瘾是一个主要的公共卫生问题。大约8.3%的人口需要治疗成瘾 2013年。可卡因是一种常用的非法药物，有10%-12%的人口滥用，可卡因的比例很高 让人上瘾。在青少年时期，有相当数量的男性和女性滥用或依赖可卡因。 在18岁及以上的成年人中，男性的患病率是女性的两倍。重要的是，我们 找出为什么有两倍的男性在青春期后仍在使用，并找出新的潜在治疗方法 可能对男性有利的目标。虽然我们的实验室历来研究性别差异，尤其是 针对女性吸毒的特点，这些研究提出了一种可能减轻毒品影响的新机制 吸纳雄鸟。在拟议的工作中，我们研究了一种新的机制，通过这种机制，偏好和 可卡因的动机在男性中受到不同程度的影响，但在女性中没有。雌二醇(E2)是一种重要的激素 在女性和男性的大脑中。在男性中，大脑中的E2是由睾酮通过 酶芳香酶。在两性中，E_2通过与三种类型的E_2受体(ER)之一结合起作用：S(α)， β(β)，或G蛋白受体-1(GPER-1)。先前的研究发现，雌二醇增强了可卡因诱导的 DA在背侧纹状体(DSTR)，并增强仅在女性的药物摄取。这项研究建议 将确定GPER-1的ER激活如何不同地影响男性对可卡因的偏好和动机 和雌性老鼠。我们的初步数据显示，GPER-1在雄性大鼠的DSTR中的激活阻断了条件性 对可卡因的位置偏好(CPP)，但对女性的CPP没有影响。其他初步结果发现， 激活GPER-1可以减弱可卡因诱导的雄性dstr内DA的增加，但不能减轻雌性dstr内DA的增加。 综上所述，这些结果表明，GPER-1的激活可能对奖赏具有保护作用 可卡因对雄性大鼠的影响，但对雌性大鼠没有影响。提出的实验将调查：1)性行为是否 DSTR中GPER-1受体激活的差异与对可卡因的偏好有关；2) GPER-1对可卡因诱导的雌雄大鼠DA释放的影响 雄性和雌性大鼠在获得过程中和获得后的可卡因。成瘾治疗需要有针对性 对男性和女性的治疗。这项工作将为预防和治疗成瘾开辟新的途径 提供性腺激素的性别特异性理解，神经生物学机制调节 精神刺激剂的有益特性。

Project Summary/Abstract Addiction is a major public health concern. Approximately 8.3% of the population needed treatment for addiction in 2013. Cocaine is one commonly used illicit drug that is abused by 10-12% of the population and is highly addictive. During adolescents, equivalent numbers of males and females are abusing or dependent on cocaine. In adults aged 18 and older, the prevalence is double in males compared to females. It is important that we identify why twice as many males are continuing to use after adolescence, and identify novel potential treatment targets that can be beneficial to males. While our lab has historically studied sex differences and especially the characteristics of female drug taking, the studies proposed focus on a novel mechanism that may mitigate drug taking in males. In the proposed work, we investigate a novel mechanism through which the preference and motivation for cocaine is differentially affected in males, but not females. Estradiol (E2) is an important hormone in the brains of both females and males. In males, E2 in the brain is synthesized from testosterone via the enzyme aromatase. In both sexes, E2 acts by binding to one of three types of E2 receptors (ER)s: alpha (α), beta (β), or G-protein receptor -1 (GPER-1). Previous studies have found that E2 potentiates cocaine-induced DA in the dorsal striatum (dSTR) and enhances acquisition of drug taking in females only. The studies proposed will identify how ER activation of GPER-1 differentially influences preference and motivation for cocaine in male and female rats. Our preliminary data show that activation of GPER-1 in the dSTR of male rats blocks conditioned place preference (CPP) for cocaine, but has no effect on CPP in females. Additional preliminary results find that activating GPER-1 attenuates cocaine-induced DA increases within the dSTR of males, but not females. Together, these results suggest that GPER-1 activation may have a protective effect against the rewarding effects of cocaine in male rats, but not females. The experiments proposed will investigate: 1) whether sex differences in GPER-1 receptor activation in the dSTR are related to the preference for cocaine; 2) the effect of GPER-1 on cocaine-induced DA release in male and female rats; and 3) the effect of GPER-1 on the motivation for cocaine in male and female rats during acquisition and after acquisition. Addiction treatment needs targeted treatment for males and females. This work will open new avenues for prevention and treatment of addiction by providing a sex-specific understanding of gonadal hormones the neurobiological mechanisms mediating the rewarding properties of psychostimulants.