Cocaine Addiction in Steroid Receptor Knockout Mice

类固醇受体基因敲除小鼠的可卡因成瘾

• 批准号: 7219477
• 负责人: VANYA QUINONES-JENAB
• 金额: $ 7.62万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7219477
• 关键词: behavioral /social science research tag; cocaine; drug addiction; drug interactions; estrogen receptors; gender difference; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; pharmacogenetics; progesterone receptors; sex hormones; substance abuse related behavior

DESCRIPTION (provided by applicant): in the United States of America, 36% of cocaine users are women. Accumulating evidence suggests that there are sex differences in the behavioral response to cocaine, where overall, female rats display more hyperactivity and exaggerated behavioral responses to cocaine as well as develop a longer-lasting and more robust behavioral sensitization to cocaine than male rats. These observations suggest that a complex process that depends on a wide range of physiological, neuronal, and hormonal interactions mediate cocaine-induced effects. Although great advances have been made in understanding molecular and behavioral adaptations after cocaine administration, very little is known about physiological and behavioral effects of cocaine in females. Females have a complex endocrinological profile; where sex/gonadal steroids (estrogen and progesterone) regulate the female's neuronal activity, many reproductive behaviors, and the synthesis and secretion of several neurotransmitters (including the opioid, monoamergic, and glutamatergic systems), affect neural circuitry during development and adulthood and control reward and motivational feedback systems. There is accumulating evidence which suggests that estrogen and progesterone affect cocaine-induced behavioral alterations. Our hypothesis is that estrogen and progesterone will potentiate or inhibit the behavioral, neurochemical, endocrinological and molecular responses to cocaine via activation of membrane and genomic receptor mediated mechanisms. Moreover, each steroid receptor isomer (beta - and alpha -estrogen receptor as well as A- and B-progesterone receptors) will differentially induce or inhibit cocaine responses. And this, in turn, regulates sex differences in the behavioral and subjective effects of cocaine. To test this postulate we propose two aims: (1) To allow us to use transgenic receptor knockout mice to examine the contributions of the various receptors, we will first determine whether the behavioral responses of female mice to cocaine are modulated by circulating gonadal steroids as they are in female monkeys, rats and humans. We will then use receptor knockout mice to determine how these genetic mutations affect females' responses to cocaine and the ability of estrogen and progesterone to modulate these responses. 2) Using different periods of steroid administration, different steroid antagonists, and steroid analogs, which do not activate intracellular receptors, we will examine whether these hormones are acting through membrane or classic intracellular steroid receptors. This study has obvious clinical implications since women's responses to cocaine may be modified by stage of the menstrual cycle, the use of hormone-containing drugs such as birth control pills, or whether she is menopausal. Variation in endocrine status may affect critical measures such as the tendency to administer an overdose and the development of tolerance and sensitization to cocaine. This important clinical issue in females needs further investigation.

描述（由申请人提供）：在美利坚合众国，36% 的可卡因使用者是 女性。越来越多的证据表明，对可卡因的行为反应存在性别差异，总体而言，雌性大鼠对可卡因表现出更多的过度活跃和夸张的行为反应，并且比雄性大鼠对可卡因产生更持久、更强烈的行为敏感性。这些观察结果表明，依赖于广泛的生理、神经元和激素相互作用的复杂过程介导了可卡因诱导的作用。尽管在了解可卡因给药后的分子和行为适应方面已经取得了巨大进展，但人们对可卡因对女性的生理和行为影响知之甚少。女性具有复杂的内分泌特征；性/性腺类固醇（雌激素和黄体酮）调节女性的神经元活动、许多生殖行为以及多种神经递质（包括阿片类、单胺和谷氨酸系统）的合成和分泌，影响发育和成年期间的神经回路并控制奖励和激励反馈系统。越来越多的证据表明雌激素和黄体酮会影响可卡因引起的行为改变。我们的假设是雌激素和孕激素将通过激活膜和基因组受体介导的机制来增强或抑制对可卡因的行为、神经化学、内分泌和分子反应。而且，每个 类固醇受体异构体（β-和α-雌激素受体以及A-和B-黄体酮受体）将不同地诱导或抑制可卡因反应。这反过来又调节了可卡因的行为和主观影响的性别差异。为了测试这一假设，我们提出了两个目标：（1）为了让我们能够使用转基因受体敲除小鼠来检查各种受体的贡献，我们将首先确定雌性小鼠对可卡因的行为反应是否受到循环性腺类固醇的调节，如下所示：它们存在于雌性猴子、老鼠和人类体内。然后，我们将使用受体敲除小鼠来确定这些基因突变如何影响女性对可卡因的反应以及雌激素和孕激素调节这些反应的能力。 2）使用不同时期的类固醇 不同的类固醇拮抗剂和类固醇类似物不会激活细胞内受体，我们将检查这些激素是否通过膜或经典的细胞内类固醇受体发挥作用。这项研究具有明显的临床意义，因为女性对可卡因的反应可能会因月经周期阶段、避孕药等含激素药物的使用或是否处于更年期而改变。内分泌状态的变化可能会影响关键指标，例如服用过量的倾向以及对可卡因的耐受性和敏感性的发展。女性的这一重要临床问题需要进一步研究。