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

可卡因/性激素/5HT--分子

• 批准号: 6515602
• 负责人: MARY L THOMAS
• 金额: $ 27.45万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515602
• 关键词: 3,4 methylenedioxymethamphetamine; behavioral /social science research tag; behavioral habituation /sensitization; cocaine; discrimination learning; dopamine receptor; dopamine transporter; dosage; drug addiction; estrogen receptors; estrogens; female; hormone regulation /control mechanism; laboratory rat; messenger RNA; neuropharmacology; ovariectomy; progesterone; progesterone receptors; receptor expression; serotonin; serotonin receptor; serotonin transporter; substance abuse related behavior

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.

描述：（申请人摘要） 精神兴奋剂的急性和慢性影响，例如可卡因和 安非他明衍生物，在女性中比男性更明显。 那里 有证据表明这些性别差异是荷尔蒙方面的，而不是 而非发展性的、基础性的。 该项目的长期目标是 确定调节背后的细胞和分子底物 女性性激素雌激素 (E) 和兴奋剂诱发的行为 黄体酮 (P)。 在本提案中，我们将测试以下假设： 性激素与血清素 (5-HT) 功能的相互作用奠定了 可卡因行为反应的基础；可卡因的作用 抑制 5-HT 再摄取有助于其行为效应，同时抑制 多巴胺 (DA) 再摄取被定义为主要介质。 激素水平 将使用具有以下特征的雌性大鼠组进行实验控制 接受卵巢切除术 (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 5-HT 转运蛋白稳态水平的影响 中脑中的 mRNA 以及中脑中的 5-HT1A、5-HT1B 和 5-HT2c 受体 mRNA 与奖励相关的大脑区域。 这些治疗的伴随效果 DA 转运蛋白、DA1 和 DA2 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-HT1A、5-HT1B 和 5-HT2C 受体对运动刺激（具体目标 2）和 可卡因在面对给定的情况下引起的敏化（具体目标 3） 激素环境。 在具体目标 4 中，性别的功能意义 药物歧视中将评估激素和 5-HT 相互作用 范式提供可卡因“主观”效应的动物模型。 完整的或 OVX 雌性大鼠将被训练来区分可卡因和 生理盐水和神经药理学特征将使用 在不存在和存在的情况下，特异性 5-HT 和 DA 激动剂和拮抗剂 卵巢激素。 运动刺激的比较研究， 滥用安非他明的致敏和歧视性刺激作用 衍生物（+/-）-3,4-亚甲二氧基甲基苯丙胺（MDMA）将进行 在平行组的大鼠中评估激素调节的普遍性 另一种精神兴奋剂，其行为影响被认为是 很大程度上由 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-HT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 女性对情绪和焦虑障碍的脆弱性将会增加 获得。

项目成果

Estrous cycle influence on individual differences in the response to novelty and cocaine in female rats.

发情周期对雌性大鼠对新奇事物和可卡因反应个体差异的影响。

• DOI: 10.1016/j.bbr.2005.01.004
• 发表时间: 2005
• 期刊: Behavioural brain research.
• 作者: Sell,StacyL;Dillon,AshleeM;Cunningham,KathrynA;Thomas,MaryL
• 通讯作者: Thomas,MaryL