Estrogenic regulation of cocaine sensitization

临床和临床前研究表明，可卡因依赖的流行率、治疗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。查明调和药物滥用易感性差异的机制可能有助于制定有效的治疗策略，以治疗和预防成瘾和复发。动物研究表明，在可卡因诱导的行为敏感化方面存在性别差异，其特征是反复接触可卡因后运动活动增加。敏化需要长期的 神经回路中的适应性反映了成瘾者对药物渴望的增加，促进了它在研究成瘾行为的动机成分方面的应用。在女性中，雌激素增强行为敏感化的机制尚不清楚。最近神经成像研究的数据表明，额叶皮质区域与药物渴求有关。此外，我们已经证明了阿片类药物对可卡因诱导的女性致敏的调制不同于在男性中观察到的，并且随着雌激素血浆水平的不同而变化。伏隔核内Mu阿片受体密度降低。推测雌激素通过以下途径促进可卡因的敏化：(1)放大伏隔核内的Mu阿片信号。(2)增强额叶皮质神经元对可卡因的代谢反应。功能磁共振成像(FMRI)将确定可卡因致敏的雄性和雌性大鼠以及去卵巢的雌性和雌性去卵巢大鼠在前额叶皮质和前扣带回的神经活动变化。我们将通过原位杂交、免疫组织化学、放射自显影和Mu配体诱导的~(35)S-yGTP结合以及药理操作和行为学测试来研究伏核内源性MU配体和受体。行为、药理学和神经化学数据的使用以及功能磁共振成像将为我们提供一种综合的方法来检查可卡因的影响，以及它与性腺激素状态的相关性， 在雌性的神经底物上。拟议的研究是独一无二的，因为/t是第一次 清醒的动物将被用来识别大脑中对反复注射可卡因做出反应的部位。

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.