Nass Sara R, Ohene-Nyako Michael, Hahn Yun K, Knapp Pamela E, Hauser Kurt F
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States.
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, United States.
Front Neurosci. 2022 May 4;16:804774. doi: 10.3389/fnins.2022.804774. eCollection 2022.
Opioid use disorder (OUD) is a critical problem that contributes to the spread of HIV and may intrinsically worsen neuroHIV. Despite the advent of combined antiretroviral therapies (cART), about half of persons infected with HIV (PWH) experience cognitive and emotional deficits that can be exacerbated by opioid abuse. HIV-1 Tat is expressed in the central nervous system (CNS) of PWH on cART and is thought to contribute to neuroHIV. The amygdala regulates emotion and memories associated with fear and stress and is important in addiction behavior. Notwithstanding its importance in emotional saliency, the effects of HIV and opioids in the amygdala are underexplored. To assess Tat- and morphine-induced neuropathology within the amygdala, male Tat transgenic mice were exposed to Tat for 8 weeks and administered saline and/or escalating doses of morphine twice daily (s.c.) during the last 2 weeks of Tat exposure. Eight weeks of Tat exposure decreased the acoustic startle response and the dendritic spine density in the basolateral amygdala, but not the central nucleus of the amygdala. In contrast, repeated exposure to morphine alone, but not Tat, increased the acoustic startle response and whole amygdalar levels of amyloid-β (Aβ) monomers and oligomers and tau phosphorylation at Ser396, but not neurofilament light chain levels. Co-exposure to Tat and morphine decreased habituation and prepulse inhibition to the acoustic startle response and potentiated the morphine-induced increase in Aβ monomers. Together, our findings indicate that sustained Tat and morphine exposure differentially promote synaptodendritic degeneration within the amygdala and alter sensorimotor processing.
阿片类物质使用障碍（OUD）是一个严重问题，它促使了艾滋病毒的传播，并且可能在本质上使神经艾滋病恶化。尽管联合抗逆转录病毒疗法（cART）已经出现，但大约一半的艾滋病毒感染者（PWH）仍会出现认知和情感缺陷，而阿片类物质滥用会加剧这些缺陷。在接受cART治疗的PWH的中枢神经系统（CNS）中会表达HIV-1反式激活因子（Tat），并且认为它会导致神经艾滋病。杏仁核调节与恐惧和压力相关的情绪和记忆，在成瘾行为中很重要。尽管其在情绪显著性方面很重要，但艾滋病毒和阿片类物质对杏仁核的影响尚未得到充分研究。为了评估Tat和吗啡在杏仁核内诱导的神经病理学变化，雄性Tat转基因小鼠在8周内接触Tat，并在接触Tat的最后2周每天两次（皮下注射）给予生理盐水和/或递增剂量的吗啡。接触Tat 8周会降低听觉惊吓反应以及基底外侧杏仁核中的树突棘密度，但不会降低杏仁核中央核的树突棘密度。相比之下，单独反复接触吗啡（而非Tat）会增加听觉惊吓反应以及杏仁核整体中淀粉样β蛋白（Aβ）单体和寡聚体的水平以及丝氨酸396处的tau磷酸化，但不会增加神经丝轻链水平。同时接触Tat和吗啡会降低对听觉惊吓反应的习惯化和前脉冲抑制，并增强吗啡诱导的Aβ单体增加。总之，我们的研究结果表明，持续接触Tat和吗啡会以不同方式促进杏仁核内的突触树突退化并改变感觉运动处理。
