The role of GPER-1 and addiction

项目概要/摘要 成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， 上瘾。在青少年时期，滥用或依赖可卡因的男女人数相等。 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 确定为什么两倍的男性在青春期后继续使用，并确定新的潜在治疗方法 对男性有益的目标。虽然我们的实验室在历史上研究了性别差异，特别是 女性吸毒的特点，研究建议集中在一个新的机制，可能减轻药物 接纳男性在拟议的工作中，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 芳香酶在两种性别中，E2通过结合三种类型的E2受体（ER）之一来起作用：α（α）， β或G蛋白受体-1（GPER-1）。先前的研究发现，E2增强可卡因诱导的 DA在背侧纹状体（dSTR），并增强收购的药物服用的女性。建议的研究 将确定如何ER激活GPER-1差异影响偏好和动机的可卡因在男性 雌性老鼠我们的初步数据表明，雄性大鼠dSTR中GPER-1的激活阻断了条件反射， 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减弱可卡因诱导的雄性dSTR内DA增加，但对雌性无影响。 总之，这些结果表明，GPER-1的激活可能对奖励具有保护作用。 可卡因对雄性大鼠的影响，而不是雌性大鼠。这些实验将研究：1）性是否 dSTR中GPER-1受体活化的差异与可卡因的偏好有关; 2） GPER-1对可卡因诱导的雄性和雌性大鼠DA释放的影响; 3）GPER-1对动机的影响 可卡因在雄性和雌性大鼠收购期间和收购后。成瘾治疗需要有针对性 治疗男性和女性。这项工作将为预防和治疗成瘾开辟新的途径， 提供了一个性别特异性的了解性腺激素的神经生物学机制介导的 精神兴奋剂的奖励特性

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.