HIV/COCAINE NEUROTOXICITY IN FEMALES

妇女现在是增长最快的人口之一， 感染了艾滋病病毒吸毒在这种疾病的传播中起主要作用 妇女：46%的妇女艾滋病病例直接归因于 注射吸毒，而男性只有22%。此外，性别 对精神兴奋剂的反应差异（即，女性更敏感 可卡因和安非他明）在动物和人类中均有报告; 然而，这些性别差异背后的生物学机制， 艾滋病毒感染和精神兴奋剂仍然在很大程度上无法解释， 科学地脱衣服拟议的方案提出了一个主要问题： 生物性别差异n对（重复）可卡因的反应 易受艾滋病毒诱导的神经毒性的女性？我们的假设是：雌激素 将作为重复静脉注射可卡因的联合作用的保护剂 给药和GP 120/达特神经毒性。首先，我们将确定 类固醇激素对GP 120/达特的联合作用具有神经保护作用 和可卡因。其次，我们将确定 雌激素调节对艾滋病病毒反应的性别差异表达 成年后的神经毒性具体来说，我们将测试雌激素 调节长期接触的雌性动物的gp 120和达特神经毒性 可卡因。我们成功地开发了一种创新的，技术简单的， 经济实用的重复给药的栓系技术 可卡因IV自由移动组圈养，大鼠。详细药代动力学 分析表明，静脉给药后可卡因水平迅速达到峰值， 大鼠，这与在人类中观察到的相似。临床上使用这个 相关IV啮齿动物给药模型，我们将确定药代动力学 这些因素有助于增加雌性动物对 尼古丁的影响第三，使用这种临床相关的静脉注射可卡因 啮齿动物给药模型，我们将确定gp 120和达特是否产生 雌性动物中多巴胺能神经毒性和受体变化 慢性可卡因我们的啮齿动物模型，静脉注射可卡因， 蛋白质神经毒性，是创新的，将转化为重要的 药物滥用和艾滋病等妇女健康问题。这项研究的目的是 为有效的基于生物学的性别特异性 艾滋病毒和可卡因成瘾的治疗策略。

Women now constitute one of the fastest growing populations becoming infected with HIV. Drug use plays a major role in the spread of this disease in women: 46 percent of women's AIDS cases are directly attributable to injection drug use, vs. only 22 percent of cases in men. In addition, gender differences in response to psychostimulants (i.e., females are more sensitive to cocaine and amphetamines) have been reported both in animals and humans; however, the biological mechanisms which underlie these gender differences to HIV infection and psychostimulants remain for the most part, unexplained and undressed scientifically. The proposed program poses the major question: are biological gender differences n responsiveness to (repeated) cocaine predisposing females ot HIV-induced neurotoxicity? Our hypothesis is: Estrogens will act as protective agents fot he combined effects of repeated IV cocaine administration and gp120/tat neurotoxicity. First, we will determine whether steroid hormones are neuroprotective against the combined effects of gp120/tat and cocaine in cultured human fetal neurons. Second, we will determine whether estrogen regulate the expression of gender differences in response to HIV neurotoxicity in adulthood. Specifically, we will test the ability of estrogen to modulate gp120 and tat neurotoxicity in female animals chronically exposed to cocaine. We have successfully developed an innovative, technically simple, economical and practical on-tethered technique for repeatedly administering cocaine IV to freely moving group-housed, rats. Detailed pharmacokinetic analysis has demonstrated rapidly peaking cocaine levels following IV dosing in rats, which is similar to that observed in humans. Using this clinically relevant IV rodent dosing model, we will determine whether pharmacokinetic factors contribute to the increased sensitivity of female animals to the effects of nicotine. Third, using this clinically relevant IV cocaine rodent-dosing model, we will determine whether gp120 and tat produce dopaminergic neurotoxicity and receptor alterations in female animals following chronic cocaine. Our rodent model of IV cocaine, in combination with HIV protein neurotoxicity, is innovative and will be translational to the important woman's health issues of drug abuse and AIDS. The goal of this research is to provide potential insight into effective biologically-based gender-specific treatment strategies for HIV and cocaine addiction.