The majority of HIV+ patients present with neuroendocrine dysfunction and ~50% experience co-morbid neurological symptoms including motor, affective, and cognitive dysfunction, collectively termed neuroHIV. In preclinical models, the neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat), promotes neuroHIV pathology that can be exacerbated by opioids. We and others find gonadal steroids, estradiol (E2) or progesterone (P4), to rescue Tat-mediated pathology. However, the combined effects of Tat and opioids on neuroendocrine function and the subsequent ameliorative capacity of gonadal steroids are unknown. We found that conditional HIV-1 Tat expression in naturally-cycling transgenic mice dose-dependently potentiated oxycodone-mediated psychomotor behavior. Tat increased depression-like behavior in a tail-suspension test among proestrous mice, but decreased it among diestrous mice (who already demonstrated greater depression-like behavior); oxycodone reversed these effects. Combined Tat and oxycodone produced apparent behavioral disinhibition of anxiety-like responding which was greater on diestrus than on proestrus. These mice made more central entries in an open field, but spent less time there and demonstrated greater circulating corticosterone. Tat increased the E2:P4 ratio of circulating steroids on diestrus and acute oxycodone attenuated this effect, but repeated oxycodone exacerbated it. Corticotropin-releasing factor was increased by Tat expression, acute oxycodone exposure, and was greater on diestrus compared to proestrus. In human neuroblastoma cells, Tat exerted neurotoxicity that was ameliorated by E2 (1 or 10 nM) or P4 (100, but not 10 nM) independent of oxycodone. Oxycodone decreased gene expression of estrogen and κ-opioid receptors. Thus, neuroendocrine function may be an important target for HIV-1 Tat/opioid interactions.

中文翻译：

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HIV-1 Tat和羟考酮的组合可激活雌性小鼠的下丘脑-垂体-肾上腺和性腺轴，并促进其精神运动，情感和认知功能障碍。

表现出神经内分泌功能障碍且约50％的大多数HIV +患者经历合并症神经系统症状，包括运动，情感和认知功能障碍，统称为NeuroHIV。在临床前模型中，神经毒性HIV-1调节蛋白（转录反式激活剂（Tat））促进了阿片类药物可加剧的神经HIV病理学。我们和其他人发现性腺类固醇，雌二醇（E2）或孕酮（P4），以挽救Tat介导的病理。然而，尚不清楚Tat和阿片类药物对神经内分泌功能以及随后的性腺类固醇改善能力的综合作用。我们发现自然循环转基因小鼠中的条件性HIV-1 Tat表达剂量依赖性地增强了羟考酮介导的精神运动行为。Tat在发情小鼠的尾部悬吊测试中增加了抑郁样行为，但在雌性小鼠（已经表现出更大的抑郁样行为）中降低了这种行为。羟考酮逆转了这些作用。Tat和羟考酮的组合产生明显的抑制焦虑样反应的行为，这种抑制作用在发情期比在发情期更大。这些小鼠在空旷的地方进入了更多的中央通道，但在那里停留的时间更少，并表现出更大的循环皮质酮。Tat增加了在类固醇上循环类固醇的E2：P4比率，急性羟考酮减弱了这种作用，但反复的羟考酮使之恶化。促肾上腺皮质激素释放因子通过Tat表达，急性羟考酮暴露而增加，并且在雌激素水平上比发情期更大。在人类神经母细胞瘤细胞中 Tat发挥的神经毒性可通过独立于羟考酮的E2（1或10 nM）或P4（100，但不是10 nM）改善。羟考酮降低雌激素和κ阿片受体的基因表达。因此，神经内分泌功能可能是HIV-1 Tat /阿片类药物相互作用的重要靶标。