Estrogenic regulation of cocaine sensitization

可卡因致敏的雌激素调节

• 批准号: 7029762
• 负责人: ANNABELL C SEGARRA
• 金额: $ 10.19万
• 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: 2004-12-08 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029762
• 关键词: Puerto Rico; autoradiography; behavior test; brain mapping; cingulate gyrus; cocaine; cooperative study; drug addiction; drug habituation; drug metabolism; drug tolerance; estrogens; frontal lobe /cortex; functional magnetic resonance imaging; gender difference; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; laboratory rat; minority institution research support; neurobiology; neurochemistry; neuropharmacology; nucleus accumbens; opioid receptor; ovariectomy; substance abuse related behavior

Clinical and preclinical studies indicate gender differences in the prevalence of cocaine dependence, response to treatment and in relapse that are unrelated to differences in the pharmacokinetics of the drug. Our long term goal is to understand the neurobiological mechanisms that contribute to gender differences in drug addiction. Identifying the mechanisms that mediate differences in vulnerability to drugs of abuse may lead to effective therapeutic strategies for the treatment and prevention of addiction and relapse. Animal studies show sex differences in cocaine-induced behavioral sensitization, characterized by an increase in locomotor activity upon repeated cocaine exposure. Sensitization involves long-term adaptations in neural circuitry that mirror the increase in drug craving in addicts, promoting its use to study motivational components of addictive behavior. In females, estrogen potentiates behavioral sensitization by mechanisms still unclear. Data from recent neuroimaging studies implicate frontal cortical areas in drug craving. Moreover, we have shown that opioid modulation of cocaine-induced sensitization in females is different from that observed in males and varies with estrogen plasma levels. A decrease in mu opioid receptor density in the nucleus accumbens was also observed. It is hypothesized that estrogen facilitates cocaine sensitization by: (1) amplifying mu opioid signaling in the nucleus accumbens. (2) potentiating the metabolic response of frontal cortical neurons to cocaine. Changes in neural activity in cocaine-sensitized male and female rats as well as in ovariectomized rats with and without estrogen will be ascertained in the prefrontal cortex and anterior cingulate by functional magnetic resonance imaging (fMRI). Endogenous mu ligands and receptors in the nucleus accumbens will be studied by in situ hybridization, immunohistochemistry, autoradiography and mu-ligand induced 35S yGTP binding and by pharmacological manipulations and behavioral testing. The use of behavioral, pharmacological and neurochemical data together with fMRI will provide us with an integrated approach to examine the effects of cocaine, and its correlation with gonadal hormonal status, on neural substrates of the female. The proposed research is unique since/t is the first time that conscious awake animals will be used to identify sites in the brain that respond to repeated cocaine administration.

临床和临床前研究表明，可卡因依赖流行率、对治疗的反应和复发率存在性别差异，这与药物的药代动力学差异无关。我们的长期目标是了解导致药物成瘾性别差异的神经生物学机制。查明在易受药物滥用影响方面存在差异的调节机制，可能有助于制定治疗和预防成瘾和复吸的有效治疗战略。动物研究表明，可卡因诱导的行为敏化的性别差异，其特征是在重复接触可卡因后自发活动增加。致敏涉及长期 神经回路的适应反映了成瘾者对药物渴望的增加，促进其用于研究成瘾行为的动机成分。在女性中，雌激素增强行为敏感化的机制尚不清楚。最近的神经影像学研究数据表明，额叶皮质区与药物渴求有关。此外，我们已经表明，阿片类药物调制可卡因诱导的致敏作用在女性中是不同的，从男性中观察到的，并与雌激素血浆水平。还观察到丘脑核中μ阿片受体密度降低。据推测，雌激素通过以下方式促进可卡因致敏：（1）放大丘脑核中的μ阿片样物质信号传导。(2)增强额叶皮层神经元对可卡因的代谢反应。可卡因致敏的雄性和雌性大鼠以及卵巢切除大鼠（有和无雌激素）的神经活动变化将通过功能性磁共振成像（fMRI）在前额叶皮层和前扣带回中确定。将通过原位杂交、免疫组织化学、放射自显影和mu-配体诱导的35 S yGTP结合以及药理学操作和行为测试来研究髓核中的内源性mu配体和受体。使用行为，药理学和神经化学数据与功能磁共振成像将为我们提供一个综合的方法来检查可卡因的影响，及其与性腺激素状态的相关性， 雌性的神经基质这项研究是独一无二的，因为/t是第一次 将使用清醒的动物来鉴定脑中对重复给予可卡因有反应的部位。