Dysregulation of dopamine neurotransmission has been linked to the development of human immunodeficiency virus (HIV)- associated neurocognitive disorder (HAND). To investigate the mechanisms underlying this phenomenon, this study used an inducible HIV-1 transactivator of transcription (Tat) transgenic (iTat-tg) mouse model, which demonstrates brain-specific Tat expression induced by administration of doxycycline. We found that induction of Tat expression in the iTat-tg mice for either 7 or 14 days resulted in a decrease (~30%) in the Vmax of [3H] dopamine uptake via both the dopamine transporter (DAT) and norepinephrine transporter (NET) in the prefrontal cortex (PFC), which was comparable to the magnitude (~35%) of the decrease in Bmax for [3H]WIN 35,428 and [3H]nisoxetine binding to DAT and NET, respectively. The decreased Vmax was not accompanied by a reduction of total or plasma membrane expression of DAT and NET. Consistent with the decreased Vmax for DAT and NET in the PFC, the current study also found an increase in the tissue content of DA and dihydroxyphenylacetic acid in the PFC of iTattg mice after 7 days' administration of doxycycline. Electrophysiological recordings in layer V pyramidal neurons of the prelimbic cortex from iTat-tg mice found a significant reduction in action potential firing, which was not sensitive to selective inhibitors for DAT and NET, respectively. These findings provide a molecular basis for using the iTat-tg mouse model in the studies of NeuroHIV. Determining the mechanistic basis underlying the interaction between Tat and DAT/NET may reveal novel therapeutic possibilities for preventing the increase in comorbid conditions as well as HAND. SIGNIFICANCE STATEMENT Human immunodeficiency virus (HIV)-1 infection disrupts dopaminergic neurotransmission, leading to HIV-associated neurocognitive disorders (HANDs). Based on our in vitro and in vivo studies, dopamine uptake via both dopamine and norepinephrine transporters is decreased in the prefrontal cortex of HIV-1 Tat transgenic mice, which is consistent with the increased dopamine and dihydroxyphenylacetic acid contents in this brain region. Thus, these plasma membrane transporters are an important potential target for therapeutic intervention for patients with HAND.
|Number of pages||11|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Aug 1 2020|
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health National Institute on Drug Abuse [Grants R01 DA035714 and R21 DA041932] (to J.Z.), [Grant R01 DA041513] (to P.I.O.), and [Grant P50 DA05312] (to M.T.B). https://doi.org/10.1124/jpet.120.266023. s This article has supplemental material available at jpet.aspetjournals.org.
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.
ASJC Scopus subject areas
- Molecular Medicine