Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia, USA.
J Neurochem. 2024 Mar;168(3):185-204. doi: 10.1111/jnc.16057. Epub 2024 Feb 3.
Despite the advent of combination anti-retroviral therapy (cART), nearly half of people infected with HIV treated with cART still exhibit HIV-associated neurocognitive disorders (HAND). HAND can be worsened by co-morbid opioid use disorder. The basal ganglia are particularly vulnerable to HIV-1 and exhibit higher viral loads and more severe pathology, which can be exacerbated by co-exposure to opioids. Evidence suggests that dopaminergic neurotransmission is disrupted by HIV exposure, however, little is known about whether co-exposure to opioids may alter neurotransmitter levels in the striatum and if this in turn influences behavior. Therefore, we assayed motor, anxiety-like, novelty-seeking, exploratory, and social behaviors, and levels of monoamines and their metabolites following 2 weeks and 2 months of Tat and/or morphine exposure in transgenic mice. Morphine decreased dopamine levels, but significantly elevated norepinephrine, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid, which typically correlated with increased locomotor behavior. The combination of Tat and morphine altered dopamine, DOPAC, and HVA concentrations differently depending on the neurotransmitter/metabolite and duration of exposure but did not affect the numbers of tyrosine hydroxylase-positive neurons in the mesencephalon. Tat exposure increased the latency to interact with novel conspecifics, but not other novel objects, suggesting the viral protein inhibits exploratory behavior initiation in a context-dependent manner. By contrast, and consistent with prior findings that opioid misuse can increase novelty-seeking behavior, morphine exposure increased the time spent exploring a novel environment. Finally, Tat and morphine interacted to affect locomotor activity in a time-dependent manner, while grip strength and rotarod performance were unaffected. Together, our results provide novel insight into the unique effects of HIV-1 Tat and morphine on monoamine neurochemistry that may underlie their divergent effects on motor and exploratory behavior.
尽管联合抗逆转录病毒疗法 (cART) 的出现，近一半接受 cART 治疗的 HIV 感染者仍表现出与 HIV 相关的神经认知障碍 (HAND)。共病阿片类药物使用障碍会使 HAND 恶化。基底神经节特别容易受到 HIV-1 的影响，并且表现出更高的病毒载量和更严重的病理学，而与阿片类药物的共同暴露则会加剧这种情况。有证据表明，HIV 暴露会破坏多巴胺能神经传递，但尚不清楚共暴露于阿片类药物是否会改变纹状体中的神经递质水平，如果这种情况反过来又会影响行为。因此，我们检测了运动、焦虑样、寻求新奇、探索和社交行为，以及在转基因小鼠中暴露于 Tat 和/或吗啡 2 周和 2 个月后单胺及其代谢物的水平。吗啡降低了多巴胺水平，但显著升高了去甲肾上腺素、多巴胺代谢物二羟苯乙酸 (DOPAC) 和高香草酸 (HVA) 以及 5-羟色胺代谢物 5-羟吲哚乙酸，这通常与运动行为增加相关。Tat 和吗啡的组合改变了多巴胺、DOPAC 和 HVA 的浓度，具体取决于神经递质/代谢物和暴露时间，但对中脑酪氨酸羟化酶阳性神经元的数量没有影响。Tat 暴露增加了与新同类动物互动的潜伏期，但不影响其他新物体，表明病毒蛋白以依赖于上下文的方式抑制探索行为的启动。相比之下，与先前发现的阿片类药物滥用会增加寻求新奇行为的结果一致，吗啡暴露增加了探索新环境的时间。最后，Tat 和吗啡以时间依赖的方式相互作用，影响运动活性，而握力和旋转棒性能不受影响。总之，我们的研究结果为 HIV-1 Tat 和吗啡对单胺神经化学的独特影响提供了新的见解，这可能是它们对运动和探索行为产生不同影响的基础。
