Gender Differences in Stimulant Action

兴奋剂作用的性别差异

• 批准号: 6917915
• 负责人: Cynthia M Kuhn
• 金额: $ 34.25万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917915
• 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）：大约三分之一的可卡因成瘾者为女性。他们很早就开始使用可卡因，对可卡因的某些作用更敏感，并且更快地发展成依赖。啮齿类动物与这种模式有一些相似之处：可卡因会引起可卡因刺激的运动更大程度地增加，雌性老鼠更努力地增强可卡因，并且细胞外多巴胺比雄性老鼠增加更多。我们的初步研究结果表明，发育时期接触性腺类固醇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以及这些系统介导的对精神运动兴奋剂的行为反应的基础。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。为了确定何时发挥类固醇作用，雄性和雌性大鼠将在出生后第 2 天、青春期前第 25 天或成年时进行性腺切除，并在出生后第 70 天确定可卡因刺激的运动和电刺激的多巴胺溢出。类固醇介导这些作用，幼鼠将接受媒介物、睾酮或雌激素拮抗剂 ICI82780（雌性）、芳香酶的治疗在产后早期或青春期期间使用抑制剂或雄激素拮抗剂氟他胺（男性），并将评估相同的依赖性措施。最后，为了评估类固醇的组织效应如何表现，将在相同的治疗后测定伏隔核和尾状核中多巴胺神经元的数量、神经支配密度、多巴胺含量和电刺激多巴胺释放。这些研究应该深入了解影响人类多巴胺神经元功能相关疾病（包括帕金森病和精神兴奋剂成瘾）性别差异的潜在生物学机制。