Estrogen and Cocaine Sensitization in the Female Rat

雌性大鼠的雌激素和可卡因致敏作用

• 批准号: 6766989
• 负责人: ANNABELL C SEGARRA
• 金额: $ 17.22万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6766989
• 关键词: behavioral /social science research tag; behavioral habituation /sensitization; cocaine; conditioning; craving; dopamine; drug abuse; estrogens; functional magnetic resonance imaging; hormone regulation /control mechanism; laboratory rat; nucleus accumbens; opioid receptor; receptor binding

Drug addiction is a national health problem. Interestingly, men and women have different sensitivities to the development of cocaine addiction that are unrelated to differences in the pharmacokinetics of the drug. There is substantial literature pointing to estrogen as a critical chemical signal affecting cocaine sensitization in the female. The studies in this proposal are designed to elucidate estrogen's mechanism of action in cocaine sensitization. It is hypothesized that estrogen facilitates cocaine sensitization by: (1) sensitizing components of the mesocorticolimbic system to repeated cocaine administration (2) altering the interaction between the opioid and dopaminergic systems. Previous studies from our laboratory indicate that estrogen and opioids interact to regulate the behavioral response to cocaine in the female rat. To investigate the mechanisms involved we have formulated the following specific aims: (1) It is hypothesized that estrogen facilitates cocaine sensitization by blunting cocaine-induced neuronal activation in rostral mesocorticolimbic brain structures such as the nucleus accumbens (NAc) and prefrontal cortex. (2 and 3) It is anticipated that repeated cocaine enhances mu and decreases kappa opioid receptor function in the nucleus accumbens. To address specific aim 1, ovariectomized rats without (OVX) and with (OVX-EB) estrogen will be injected for 5 days with cocaine hydrochloride (15 mg/kg), challenged on day 13 with the same dose of cocaine and brain activity monitored by fMRI. To address specific aims 2 and 3, we will measure changes in mu and kappa opioid receptor binding in OVX and OVX-EB rats in response to acute and repeated cocaine and after withdrawal and reinstatement. An additional group of animals will be treated with specific mu and kappa opioid agonists and antagonists during repeated cocaine administration and after reinstatement and tested for behavioral sensitization. The progressive daily increase in locomotor activity elicited by the same dosage of cocaine will be used as an indicator of cocaine sensitization. Opioid ligands that induce changes in behavioral sensitization will be used in experiments that image cocaine-induced changes in BOLD signal by functional MRI (fMRI). At the conclusion of the in vivo studies, the brains will be studied for assessment of opioid (mu and kappa) receptors by regular and functional autoradiography. The proposed research is innovative because it capitalizes on the new technology of fMRI to identify sites in the brain that respond to acute and repeated cocaine administration. The results obtained will be significant because they will provide neurobiological data for the development of new therapeutic strategies in the treatment of drug addiction taking into consideration the differences in the physiology and biochemistry of men and women.

吸毒成瘾是一个全国性的健康问题。有趣的是，男性和女性对可卡因成瘾的敏感性不同，这与药物的药代动力学差异无关。大量文献指出雌激素是影响女性可卡因致敏的关键化学信号。本研究旨在阐明雌激素在可卡因致敏中的作用机制。据推测，雌激素通过以下方式促进可卡因致敏：（1）使中皮质边缘系统的成分对重复给予可卡因敏感（2）改变相互作用 阿片和多巴胺系统之间的联系我们实验室以前的研究表明，雌激素和阿片类药物相互作用，调节雌性大鼠对可卡因的行为反应。为了研究其机制，我们制定了以下具体目标：（1）假设雌激素通过减弱可卡因诱导的吻侧中皮质边缘脑结构（如中脑核（NAc）和前额皮质）神经元激活来促进可卡因致敏。（2和3）预期重复可卡因增强了延髓核中的μ阿片受体功能并降低了κ阿片受体功能。为了解决具体的目标1，将用盐酸可卡因（15 mg/kg）注射没有（OVX）和具有（OVX-EB）雌激素的卵巢切除大鼠5天，在第13天用相同剂量的可卡因攻击， 通过功能磁共振成像监测大脑活动为了解决具体目标2和3，我们将测量OVX和OVX-EB大鼠对急性和重复可卡因的反应以及戒断和恢复后μ和κ阿片受体结合的变化。另外一组动物将在重复可卡因给药期间和恢复后用特异性μ和κ阿片样物质激动剂和拮抗剂处理，并检测行为致敏性。由相同剂量的可卡因引起的自发活动的每日逐渐增加将被用作可卡因致敏的指标。诱导行为敏化变化的阿片样物质配体将用于通过功能性MRI（fMRI）成像可卡因诱导的BOLD信号变化的实验中。在体内研究结束时，将通过常规和功能性放射自显影术研究大脑以评估阿片类（mu和kappa）受体。这项研究是创新的，因为它利用了功能磁共振成像的新技术来识别大脑中对急性和重复服用可卡因做出反应的部位。所获得的结果将是重要的，因为它们将提供神经生物学数据，用于在考虑到男女生理和生物化学差异的情况下制定治疗吸毒成瘾的新治疗策略。