The Effects of Estradiol on Cocaine Intake in Female HR and LR Rats

描述（由申请人提供）：性别差异和个体差异影响物质使用障碍的发展。例如，可卡因成瘾的男子人数较多，而妇女在较早的年龄就对可卡因成瘾，对可卡因的依赖性比男子更大。同样，雌性大鼠比雄性大鼠更快地获得可卡因自我给药，并且将比雄性大鼠自我给药更多的可卡因。这些性别差异至少部分是由于雌二醇。当雌性大鼠的雌二醇水平高时，它们会比雌二醇水平低时自我施用更多的可卡因。除了性别差异和雌二醇的影响外，个体差异也会影响人类和大鼠的可卡因成瘾。具有寻求新奇的个性特征的人更有可能尝试毒品，因此，发展成瘾。对新环境表现出高运动行为反应的大鼠（高反应者，HR）表现出与人类新奇寻求者相似的倾向，因为它们将比对新环境表现出低运动行为反应的大鼠（低反应者，LR）更快地获得可卡因的自我给药行为。因此，具有HR表型的大鼠被用作人类新奇寻求者的模型。我的研究使用的大鼠已经选择性繁殖的HR和LR表型。我的数据表明，选择性繁殖的HR男性和女性将获得可卡因自我管理比LR男性和女性更快。此外，雌性HR大鼠比HR雄性大鼠、LR雄性大鼠和LR雌性大鼠摄入更多的可卡因。使用相同的大鼠品系，我打算测试雌二醇和表型差异对雌性HR和LR大鼠可卡因自我给药的影响，以确定雌二醇在上述差异中起什么作用。该提案的具体目标包括：具体目标1，将确定雌二醇与HR和LR表型如何相互作用以影响雌性大鼠获得可卡因自我给药;具体目标2，将确定雌二醇与HR和LR表型如何影响雌性大鼠服用可卡因的动机;具体目标3将确定雌二醇和HR或LR表型如何影响雌性大鼠可卡因自我给药行为的恢复。为了研究这些目标，我将使用选择性繁殖的HR或LR表型的雌性大鼠。 公共卫生相关性：我提出这个建议的主要目的是更好地了解激素（如雌二醇）和个人人格特质如何影响女性的物质使用障碍。这对于治疗妇女的药物使用障碍和制定预防这类障碍的方案至关重要，而预防这类障碍对改善公共卫生至关重要。

DESCRIPTION (provided by applicant): Sex differences and individual differences influence the development of substance use disorders. For example, a greater number of men are addicted to cocaine, yet women get addicted to cocaine at earlier ages and demonstrate a greater dependence for cocaine than men. Similarly, female rats acquire cocaine self-administration more rapidly than males and will self-administer more cocaine than males. These sex differences are at least in part due to estradiol. When estradiol is high in female rats, they will self-administer more cocaine than when estradiol levels are low. In addition to sex differences and the effects of estradiol, individual differences influence cocaine addiction in humans and rats. Persons with the individual personality trait for novelty seeking are more likely to try drugs and, therefore, develop addictions. Rats that show high locomotor behavior in response to a novel environment (high responders, HR) show similar tendencies to human novelty seekers in that they will acquire self-administration behavior for cocaine more rapidly than rats that show a low locomotor behavioral response to a novel environment (low responders, LR). Therefore, rats with the HR phenotype are used as a model for human novelty seekers. My studies use rats that have been selectively-bred for the HR and LR phenotypes. My data demonstrate that selectively-bred HR males and females will acquire cocaine self-administration more rapidly than LR males and females. In addition, female HR rats take more cocaine than HR males, LR males and LR females. Using this same line of rats, I intend to test for the effects of estradiol and phenotype differences on cocaine self-administration in female HR and LR rats in order to determine what part estradiol plays in the afore mentioned differences. The specific aims of this proposal include: Specific Aim 1, which will determine how estradiol and the HR and LR phenotypes interact to influence on acquisition of cocaine self-administration in female rats; Specific Aim 2, which will determine how estradiol and the HR and LR phenotypes impact motivation to take cocaine in female rats; and Specific Aim 3 will determine how estradiol and the HR or LR phenotypes influence reinstatement of cocaine self-administration behavior in female rats. To investigate these aims I will be using female rats that are selectively-bred for the HR or LR phenotype. PUBLIC HEALTH RELEVANCE: My main objective for this proposal is to better understand how hormones (e.g. estradiol) and individual personality traits influence substance use disorders in females. This is crucial for the treatment of substance use disorders in women and for the development of programs for the prevention of such disorders, which is crucial to improving public health.