COCAINE/SEX HORMONE/5HT--MOLECULAR & BEHAVIORAL ANALYSES

描述：(申请人摘要) 精神刺激剂的急性和慢性影响，如可卡因和 苯丙胺衍生物，女性比男性更明显。那里 有证据表明，这些性别差异是荷尔蒙方面的 而不是发展的，基础的。这个项目的长期目标是 确定构成调制的细胞和分子底物 女性性激素雌激素(E)和雌激素对兴奋剂诱导行为的影响 孕酮(P)。在目前的提案中，我们将检验以下假设 性激素与5-羟色胺(5-HT)功能的相互作用奠定了 可卡因行为反应的基础；可卡因对 抑制5-羟色胺再摄取有助于其行为效应 多巴胺(DA)的再摄取被定义为主要的介体。激素水平 将使用一组雌性大鼠进行实验控制， 接受卵巢摘除(OVX)，用或不用E和P替代。 具体目标1，将使用分子生物学方法来评估 卵巢类固醇对稳态5-羟色胺转运体水平的影响 中脑组织中5-HT1A、5-HT1B和5-HT2C受体基因的表达 与奖赏相关的大脑区域。这些治疗的相伴效应对 多巴胺转运体、DA1和DA2受体、E和P的mRNA水平 受体也将被确定。行为和药理学工具 将用于评估5-HT1A、5-HT1B和 5-HT2C受体对运动刺激的作用(特异靶2)和 可卡因面对受试者的敏化(特异靶3) 荷尔蒙环境。在具体目标4中，性的功能意义 激素和5-羟色胺的相互作用将在药物鉴别中进行评估 提供可卡因“主观”影响的动物模型。 完整的或卵巢切除的雌性大鼠将接受训练，以区分可卡因和 生理盐水和神经药理学特征将使用 特异性5-羟色胺和多巴胺激动剂和拮抗剂 卵巢激素。运动刺激性的比较研究， 滥用苯丙胺的敏化和辨别刺激效应 将进行(+/-)-3，4-亚甲基二氧基甲基苯丙胺(MDMA) 在平行的大鼠组中评估激素调节的普遍性 另一种精神刺激剂，其行为影响被认为是 这在很大程度上是由5-羟色胺机制介导的。这些研究的结果 将提供有关基本机制的重要信息 类固醇-5-羟色胺相互作用和性别差异在 对精神刺激剂的反应性。因此，对 女性药物依赖的潜在治疗策略以及 女性对情绪和焦虑症的易感性将增加 获得。

DESCRIPTION: (Applicant's Abstract) The acute and chronic effects of psychostimulants, such as cocaine and amphetamine derivatives, are more pronounced in females than males. There is evidence to suggest that these gender differences are hormonally, rather than developmentally, based. The long-term goal of this project is to determine the cellular and molecular substrates that underlie the modulation of stimulant-induced behaviors by the female sex hormones estrogen (E) and progesterone (P). In the present proposal, we will test the hypothesis that the interaction of sex hormones with serotonin (5-HT) function lays the foundation for the behavioral response to cocaine; the actions of cocaine to inhibit 5-HT reuptake contribute to its behavioral effects while inhibition of dopamine (DA) reuptake is defined as a primary mediator. Hormone levels will be controlled experimentally using groups of female rats that have undergone ovariectomy (OVX), with or without replacement with E and P. In Specific Aim 1, molecular biology approaches will be used to assess the impact of ovarian steroids on steady-state levels of the 5-HT transporter mRNA in midbrain and 5-HT1A, 5-HT1B, and 5-HT2c receptor mRNA in reward-relevant brain areas. The concomitant effects of these treatments on levels of mRNA for DA transporter, DA1 and DA2 receptors, and E and P receptors will also be determined. Behavioral and pharmacological tools will be used to assess the relative contribution of 5-HT1A, 5-HT1B, and 5-HT2C receptors to the locomotor stimulation (Specific Aim 2) and sensitization (Specific Aim 3) induced by cocaine in the face of given hormone environments. In Specific Aim 4, the functional significance of sex hormone and 5-HT interactions will be assessed in the drug discrimination paradigm to provide an animal model of the "subjective" effects of cocaine. Intact or OVX female rats will be trained to discriminate cocaine from saline and the neuropharmacological profile will be investigated using specific 5-HT and DA agonists and antagonists in the absence and presence of ovarian hormones. A comparative study of the locomotor stimulatory, sensitization and discriminative stimulus effects of the abused amphetamine derivative (+/-)-3,4-methylenedioxymethamphetamine (MDMA) will be conducted in parallel groups of rats to assess the generality of hormonal regulation to another psychostimulant, one whose behavioral effects are thought to be mediated in large part by 5-HT mechanisms. The results of these studies will provide important information concerning the fundamental mechanisms underlying both steroid-5-HT interactions and gender differences in the responsivity to psychostimulants. As a consequence, new insight into potential therapeutic strategies for drug dependence in women as well as the enhanced vulnerability of women to mood and anxiety disorders will be obtained.