Gender Differences in Stimulant Action

兴奋剂作用的性别差异

• 批准号: 6775662
• 负责人: Cynthia M Kuhn
• 金额: $ 30.8万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-03-15 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6775662
• 关键词: androgen inhibitor; animal puberty; behavioral /social science research tag; central nervous system stimulants; chordate locomotion; cocaine; developmental neurobiology; dopamine; drug addiction; estrogens; gender difference; hormone regulation /control mechanism; immunocytochemistry; laboratory rat; neuroendocrine system; progesterone; prosencephalon; psychomotor function; psychopharmacology; steroids; substance abuse related behavior; tamoxifen; testosterone; tyrosine 3 monooxygenase

DESCRIPTION (provided by applicant): Women comprise about one third of cocaine addicts. They start using cocaine earlier in life, are more sensitive to some cocaine effects and progress to dependence more rapidly. Rodents show some similarities to this pattern: cocaine elicits greater increases in cocaine-stimulated locomotion, females work harder for cocaine reinforcement and extracellular dopamine rises more than in male rats. Our preliminary findings suggest that developmental exposure to gonadal steroids contributes to sex differences in cocaine action. The purpose of this proposal is to investigate the basis for the organizational effect of gonadal steroids on forebrain dopamine systems and the behavioral response to psychomotor stimulants mediated by these systems. We will test the hypothesis that sex differences in cocaine effects reflect anatomical or functional differences in dopamine neurons established during ontogeny. To determine when steroid effects are exerted, male and female rats will be gonadectomized on postnatal day 2, prepubertally on day 25 or in adulthood, and cocaine-stimulated locomotion and electrically-stimulated dopamine overflow will be determined on postnatal day 70. To evaluate which steroid mediates these effects, rat pups will be treated with vehicle, testosterone or estrogen antagonist ICI82780 (females), an aromatase inhibitor or androgen antagonist flutamide (males) during the early postnatal window or during puberty and the same dependent measures will be assessed. Finally, to evaluate how organizational effects of steroids are manifested, the number of dopamine neurons, density of innervation, dopamine content and electrically-stimulated dopamine release in nucleus accumbens and caudate nucleus will be determined following the same treatments. These studies should provide insight into potential biologic mechanisms that influence gender differences in diseases related to dopamine neuronal function in humans including Parkinson's disease and psychostimulant addiction.

描述（由申请人提供）：妇女约占可卡因成瘾者的三分之一。他们开始生命早期使用可卡因，对某些可卡因效应和进步更快地依赖性更快。啮齿动物与这种模式显示出一些相似之处：可卡因引起的可卡因刺激的运动增加，女性在可卡因增强方面更加努力地工作，而细胞外多巴胺的上升比雄性大鼠更大。我们的初步发现表明，性腺类固醇的发育暴露会导致可卡因作用的性别差异。该提案的目的是研究性腺类固醇对前脑多巴胺系统的组织效应的基础，以及这些系统介导的心理运动刺激物的行为反应。我们将检验以下假设：可卡因效应的性别差异反映了个体发育过程中建立的多巴胺神经元的解剖或功能差异。为了确定何时施加类固醇的作用，将在出生后第2天，在第25天或成年期间对雄性和雌性大鼠进行性腺切除术，以及可卡因刺激的运动和电刺激的多巴胺溢流将在产后第70天确定，以评估这些类固醇的效果。 ICI82780（雌性），芳香酶抑制剂或雄激素拮抗剂氟二酰胺（男性）在早期窗口或青春期期间以及相同的依赖措施。最后，为了评估类固醇的组织作用如何表现，多巴胺神经元的数量，神经元的密度，多巴胺含量和伏隔核中的电刺激多巴胺释放的数量将在同一处理后确定。这些研究应洞悉潜在的生物学机制，这些机制影响人类中与多巴胺神经元功能有关的性别差异，包括帕金森氏病和精神刺激成瘾。