Integrating preclinical models to develop converging mechanistic data in co-occuring HIV and substance use

项目摘要 艾滋病毒使用障碍（CUD）与艾滋病毒感染高度共病，其特征是高倾向性 即使在长期禁欲后也会复发。随着抗逆转录病毒疗法（ART）的成功， 死亡率大幅下降，导致接受抗逆转录病毒治疗的慢性艾滋病毒感染者人数不断增加， 成年人在美国。HIV感染和ART都可能与药物暴露相互作用，改变神经生物学， 从而产生行为和生物学上不同的病症，并需要新的靶向药物 减少可卡因复吸的战略。对毒品的渴望可能促使复吸。期间 长期戒断反复接触可卡因，可卡因寻求行为变得渐进 更强烈，表明“渴望的孵化”。发展战略，以减少这种渴望有强大的 减少复发相关行为的潜力。因此，本提案中的研究旨在补充 通过调查进行性HIV感染和每日ART的独立和联合作用， 治疗可卡因渴望潜伏期的神经行为后遗症。皮质纹状体谷氨酸 系统是复发相关行为的关键调节器。破坏谷氨酸体内平衡， 神经炎症与暴露于可卡因或HIV感染有关。然而，联合国的影响 长期可卡因戒断和HIV对神经免疫功能和谷氨酸系统功能的影响较差 明白这项提案将调查艾滋病毒和艾滋病之间的行为和神经生物学相互作用。 在促进可卡因寻求的关键中皮质边缘结构（内侧皮层）中培养可卡因渴望 前额叶皮层（mPFC）和丘脑核（NAc））。我们将测试一个总体假设， 戒除可卡因与HIV和ART相互作用，独特地失调谷氨酸稳态， 神经免疫功能，导致可卡因寻求行为的增强。目标1将决定结果 EcoHIV感染和每日ART治疗对可卡因条件性位置偏好模型中可卡因渴求的影响 在雄性和雌性小鼠中。目的2将确定EcoHIV和每日ART对谷氨酸变化的影响 mPFC和NAc的系统标志物和神经免疫功能。这些研究的结果将补充 在父母奖概述的实验，并告知未来的研究方向，旨在阐明新的 在进行性HIV背景下治疗物质使用障碍的药物靶点， 条此外，授予这一行政补充将允许候选人-一个非常好的- 合格的西班牙裔-亚洲博士后学者-获得共病进行性艾滋病毒模型的实践培训 和可卡因暴露该奖项的结果预计将作为制定 独立的研究路线，将导致随后的奖学金和职业过渡奖的建议，由 候选人

Project Summary Cocaine use disorders (CUDs) are highly comorbid with HIV infection and are characterized by a high propensity to relapse even after protracted abstinence. With the success of antiretroviral therapies (ART), HIV-associated mortality has substantially declined, resulting in a growing population of chronically HIV-infected, ART treated adults in the United States. Both HIV infection and ART may interact with drug exposure to alter neurobiology, thus creating a behaviorally and biologically distinct condition and requiring novel, targeted pharmacotherapeutic strategies to reduce relapse to cocaine use. Relapse to drug use may be precipitated by drug craving. During protracted withdrawal from repeated cocaine exposure, cocaine-seeking behavior becomes progressively stronger, indicative of the “incubation of craving”. Development of strategies to reduce this craving have strong potential to reduce relapse-related behaviors. Thus, research in this proposal is designed to complement the parent award by investigating independent and combined effects of progressive HIV infection and daily ART treatment on the neurobehavioral sequelae of the incubation of cocaine craving. The corticostriatal glutamate system is a key regulator of relapse-related behavior. Disruption of glutamate homeostasis and neuroinflammation occur with exposure to either cocaine or HIV infection. However, the impact of combined protracted cocaine abstinence and HIV on neuroimmune function and glutamate system function is poorly understood. This proposal will investigate the behavioral and neurobiological interactions between HIV and incubated cocaine craving within key mesocorticolimbic structures that facilitate cocaine seeking (the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc)). We will test the overarching hypothesis that protracted abstinence from cocaine interacts with HIV and ART to uniquely dysregulate glutamate homeostasis and neuroimmune function, leading to potentiation of cocaine-seeking behavior. Aim 1 will determine the outcomes of EcoHIV infection and daily ART treatment on cocaine craving in a cocaine conditioned place preference model in male and female mice. Aim 2 will determine the effect of EcoHIV and daily ART on changes in glutamate system markers and neuroimmune function in the mPFC and NAc. Findings from these studies will complement the experiments outlined in the parent award and inform future research directions aimed at elucidating novel pharmacotherapeutic targets for the treatment of substance use disorders in the context of progressive HIV and ART. Further, the award of this administrative supplement will allow the candidate – an exceptionally well- qualified Hispanic-Asian postdoctoral scholar - to gain hands-on training in models of comorbid progressive HIV and cocaine exposure. Findings from the award are expected to serve as the basis for the development of an independent line of research that will lead to subsequent fellowship and career transition award proposals by the candidate.