HIV/COCAINE NEUROTOXICITY IN FEMALES

女性现在构成了增长最快的人口之一， 感染了艾滋病毒。吸毒是这种疾病传播的主要原因。 在妇女中：46%的妇女艾滋病病例直接归因于 注射吸毒，而男性只有22%的病例。此外，性别 对精神刺激剂的反应差异(即女性更敏感 可卡因和安非他明)在动物和人类中都有报道； 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刺激剂在很大程度上仍然无法解释和 科学地脱掉衣服。拟议的计划提出了主要问题：是 生物性别差异与(重复)可卡因的反应 使女性容易感染艾滋病毒引起的神经毒性？我们的假设是：雌激素 会对反复静脉注射可卡因的综合作用起到保护作用 给药和gp120/TAT神经毒性。首先，我们将确定是否 类固醇激素对gp120/Tat联合作用的神经保护作用 和可卡因在培养的人类胎儿神经元中。第二，我们将确定是否 雌激素调节HIV应答中的性别差异表达 成年期的神经毒性。具体地说，我们将测试雌激素的能力 慢性暴露雌性动物gp120和TAT神经毒性的调节 为了可卡因。我们已经成功地开发出一种创新的、技术简单的 经济实用的重复给药在线给药技术 可卡因静脉注射给自由活动的群体--大鼠。详细的药代动力学 分析表明，在静脉注射可卡因后，可卡因水平迅速达到峰值 老鼠，这与在人类身上观察到的相似。将其应用于临床 相关的大鼠静脉给药模型，我们将确定是否存在药代动力学 一些因素导致雌性动物对 尼古丁的影响。第三，使用这种临床上相关的静脉注射可卡因 啮齿动物给药模型，我们将确定gp120和tat是否产生 雌性动物的多巴胺能神经毒性和受体改变 慢性可卡因。我们的静脉注射可卡因与艾滋病毒结合的啮齿动物模型 蛋白质的神经毒性，是创新的，并将转化为重要的 妇女的健康问题，如滥用药物和艾滋病。这项研究的目标是 提供对有效的基于生物的特定性别的潜在洞察 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.