HIV/Cocaine Neurotoxicity in Females

描述（由申请人提供）：在这个竞争性的更新应用中，我们将探索雌激素化合物可能作为可卡因/HIV蛋白协同作用的保护剂，在伏隔核中产生突触损伤。这是一个与HIV-1相关神经认知障碍（HAND）相关的运动和认知功能障碍相关的关键大脑区域，被认为是中脑端多巴胺系统的主要靶点，也是前额叶起源回路的主要纹状体中转站。具体目的是：1)研究可卡因/HIV-1蛋白诱导的突触损伤和雌激素对神经可塑性的调节作用。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化合物作为hiv蛋白诱导的突触损伤的潜在雌激素受体调节剂。2)在慢性HIV-1蛋白暴露模型中，确定雌激素在反复可卡因后调节伏隔核多巴胺能突触可塑性中的作用。HIV-1蛋白+可卡因对多巴胺能神经化学的影响将在切除卵巢的雌性HIV-1转基因动物体内进行微透析评估。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中的作用及雌激素治疗效果。雌激素将用于调节可卡因和HIV-1后的认知和多巴胺标志物，为潜在的神经保护机制和治疗策略提供见解。研究将集中于量化脊柱密度变化与伏隔核中棘神经元和前额皮质神经元可塑性调节的关系。本研究的最终目的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HIV-1+特殊人群可卡因滥用后的认知和运动功能障碍（HAND）。

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.