Estrogenic regulation of cocaine sensitization

可卡因致敏的雌激素调节

• 批准号: 7774305
• 负责人: Annabell C. Segarra
• 金额: $ 15.25万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774305
• 关键词: Abstinence; Addictive Behavior; Affect; Agonist; Animals; Anterior; Area; Autoradiography; Behavioral; Binding; Brain; Cerebrovascular Circulation; Chemicals; Chronic; Clinical; Cocaine; Cocaine Dependence; Collaborations; Computer software; Conscious; Corpus striatum structure; Cues; Data; Data Analyses; Dorsal; Drug Addiction; Drug Kinetics; Endorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Estradiol Benzoate; Estrogen Replacements; Estrogens; Female; Functional Magnetic Resonance Imaging; Goals; Hormonal; Image Analysis; Immunohistochemistry; In Situ; In Situ Hybridization; Injection of therapeutic agent; Lead; Ligands; Literature; Measures; Mediating; Messenger RNA; Metabolic; Molecular Neurobiology; Motor Activity; Narcotic Antagonists; Neurons; Nucleus Accumbens; Opioid; Opioid Receptor; Opioid Receptor Binding; Pathway interactions; Pharmaceutical Preparations; Plasma; Positron; Prefrontal Cortex; Prevalence; Prevention; Property; Rattus; Receptor Activation; Regulation; Relapse; Reporting; Research; Rewards; Role; Self Administration; Sex Characteristics; Signal Transduction; Signal Transduction Pathway; Site; Symptoms; System; Testing; Therapeutic; Time; Woman; addiction; awake; behavior test; behavioral sensitization; cingulate gyrus; cocaine exposure; craving; drug craving; drug of abuse; drug withdrawal; effective therapy; in vitro Assay; innovation; male; men; mu opioid receptors; neural circuit; neuroadaptation; neurobiological mechanism; neurochemistry; neuroimaging; preclinical study; preference; programs; receptor; receptor density; relating to nervous system; response; sex; therapy development; treatment strategy

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，可卡因依赖性，对治疗的反应和复发的性别差异与药物药代动力学的差异无关。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。确定介导在滥用滥用药物的脆弱性方面差异的机制可能会导致有效的治疗策略，以治疗和预防成瘾和复发。动物研究表明，可卡因诱导的行为敏化的性别差异，其特征是重复可卡因暴露时运动活性的增加。敏化涉及长期 在神经回路中的适应，反映了成瘾者中药物渴望的增加，从而促进了其用于研究成瘾行为的动机成分的用途。在女性中，雌激素通过仍不清楚的机制增强了行为敏感性。最近的神经影像学研究的数据暗示了药物渴望的额叶皮质区域。此外，我们已经表明，女性对可卡因诱导的敏化的阿片类药物调节与在男性中观察到的敏感性不同，并且随雌激素血浆水平而变化。还观察到伏隔核中MU阿片受体密度的降低。假设雌激素通过以下方式促进可卡因敏化，（1）在伏隔核中扩增阿片类药物信号。 （2）增强额叶神经元对可卡因的代谢反应。可卡因敏感的雄性和雌性大鼠以及具有和不含雌激素的卵巢切除大鼠的神经活性的变化将在前额叶皮层中确定，并通过功能磁共振成像（fMRI）在额叶前依赖。将通过原位杂交，免疫组织化学，放射自显影和MU-LIGAND诱导35S YGTP结合以及药理学操纵和行为测试来研究伏隔核中的内源性MU配体和受体。使用行为，药理和神经化学数据以及fMRI的使用将为我们提供一种综合方法来检查可卡因的影响及其与性腺激素状态的相关性， 关于女性的神经底物。拟议的研究是独一无二的，因为/t是第一次 有意识的清醒动物将用于识别大脑中对重复可卡因给药反应的部位。