HIV‐1 Tat and morphine interactions dynamically shift striatal monoamine levels and exploratory behaviors over time

Abstract

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.