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

描述：（申请人摘要） 精神兴奋剂的急性和慢性影响，如可卡因和 安非他明衍生物，女性比男性更明显。 那里 有证据表明，这些性别差异是精神上的， 而不是发展性的 该项目的长期目标是 确定作为调节基础的细胞和分子底物 由女性性激素雌激素（E）和 孕酮（P）。 在本提案中，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-HT再摄取有助于其行为效应，而抑制 多巴胺（DA）的再摄取被定义为主要介质。 激素水平 将使用雌性大鼠组进行实验控制， 进行卵巢切除术（OVX），用或不用E和P替代。 具体目标1，分子生物学方法将用于评估 卵巢类固醇激素对5-HT转运体稳态水平的影响 中脑5-HT 1A、5-HT 1B和5-HT 2c受体mRNA 奖励相关的大脑区域。 这些治疗的伴随作用 DA转运蛋白、DA 1和DA 2受体以及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-HT 1A、5-HT 1B和 5-HT 2C受体对运动刺激的作用（特异性目标2）， 致敏作用（具体目标3） 荷尔蒙环境 在具体目标4中，性别的功能意义 激素和5-HT相互作用将在药物辨别中进行评估 范例，以提供可卡因的“主观”效果的动物模型。 将训练完整或OVX雌性大鼠区分可卡因和可卡因。 生理盐水和神经药理学特征将使用 特异性5-HT和DA激动剂和拮抗剂， 卵巢激素 运动刺激， 滥用安非他明的敏化和辨别刺激效应 将进行衍生物（+/-）-3，4-亚甲二氧基甲基苯丙胺（MDMA） 在大鼠的平行组中评估激素调节的一般性 另一种精神兴奋剂，其行为影响被认为是 大部分由5-HT机制介导。 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的基础 对精神兴奋剂的反应 因此，新的见解， 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脆弱性增加， 得到了

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.