HIV/Cocaine Neurotoxicity in Females

描述(申请人提供)：在这项竞争性的更新申请中，我们将探索一种假说，即雌激素化合物可能作为可卡因/艾滋病毒蛋白在伏隔核产生突触损伤的协同效应的保护剂，伏隔核是参与与HIV-1相关的神经认知障碍(手)相关的运动和认知功能障碍的关键大脑区域，并被公认为中脑多巴胺系统的主要靶点和额前额前起源回路的主要纹状体通路。其具体目的是：1)探讨可卡因/HIV-1蛋白诱导的突触损伤和雌激素调节神经可塑性的作用。拟议的体外实验将进一步确定雌激素活性的机制，并测试新的大豆异黄酮类化合物作为潜在的雌激素受体调节剂来治疗HIV蛋白诱导的突触损伤。2)探讨雌激素(S)对慢性HIV-1蛋白暴露模型伏隔核多巴胺能突触可塑性的调节作用。在卵巢切除的雌性HIV-1转基因动物中，将使用体内微透析来评估HIV-1蛋白+可卡因对多巴胺能神经化学的影响。将评估雌激素/大豆异黄酮+可卡因在生理条件下产生DAT功能障碍/保护的能力，并确定其行为/病理后果。3)探讨突触可塑性在HIV-1蛋白+可卡因认知行为障碍及雌激素治疗中的作用。雌激素(S)将用于调节可卡因和艾滋病毒-1之后的认知和多巴胺标记物，为潜在的神经保护机制和治疗策略提供洞察。研究将集中于量化与伏隔核、中棘神经元和前额叶皮质神经元可塑性调节相关的脊柱密度变化。这项研究的最终目标是确定敏感靶点和独特的药物干预措施(雌激素受体调节剂)，以预防艾滋病毒-1+特殊人群中滥用可卡因后的认知和运动功能障碍(手)。

DESCRIPTION (provided by applicant): In this competing renewal application, we will explore the hypothesis that estrogenic compounds may serve as protective agents for the synergistic effects of cocaine/HIV proteins on producing synaptic impairments in the nucleus accumbens, a critical brain region involved in the motor and cognitive dysfunction associated with HIV-1 associated neurocognitive disorder (HAND) and recognized as the main target of the mesotelencephalic dopamine system and the main striatal waystation for circuits of prefrontal origin. The specific aims are: 1) To investigate the role of cocaine/HIV-1 protein-induced synaptic impairment and estrogenic modulation of neuroplasticity. The proposed in vitro experiments will further determine the mechanisms of estrogenic activity and test novel soy isoflavone compounds as potential estrogen ¿-receptor modulators of HIV-protein induced synaptic impairment. 2) To determine the role of estrogen(s) in modulating nucleus accumbens dopaminergic synaptic plasticity following repeated cocaine in chronic HIV-1 protein exposure models. The effects of HIV-1 protein+cocaine on dopaminergic neurochemistry will be assessed using in vivo microdialysis in ovariectomized female HIV-1 transgenic animals. The ability of estrogen/soy isoflavones+ cocaine to produce DAT dysfunction/protection under physiological conditions will be assessed and the behavioral/pathological consequences will be determined. 3) To determine the role of synaptic plasticity in HIV-1 protein+cocaine cognitive behavioral impairments and estrogenic therapeutic effects. Estrogen(s) will be used to modulate cognition and dopamine markers following cocaine and HIV-1, providing insight into potential neuroprotective mechanisms and therapeutic strategies. Investigations will focus on quantifying spine density changes with respect to regulators of nucleus accumbens medium spiny neurons and prefrontal cortical neuronal plasticity. The ultimate goal of this research is to identify sensitive targets and unique pharmacological interventions (estrogen ¿-receptor modulators) for preventing cognitive and motor dysfunction (HAND) following cocaine abuse in HIV-1+ special populations.