TY - JOUR
T1 - [3H] Dopamine uptake through the Dopamine and Norepinephrine transporters is decreased in the prefrontal cortex of transgenic mice expressing HIV-1 transactivator of transcription protein
AU - Strauss, Matthew
AU - O'Donovan, Bernadette
AU - Ma, Yizhi
AU - Xiao, Ziyu
AU - Lin, Steven
AU - Bardo, Michael T.
AU - Ortinski, Pavel I.
AU - McLaughlin, Jay P.
AU - Zhu, Jun
N1 - Publisher Copyright:
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
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U2 - 10.1124/jpet.120.266023
DO - 10.1124/jpet.120.266023
M3 - Article
C2 - 32461322
AN - SCOPUS:85088176771
SN - 0022-3565
VL - 374
SP - 241
EP - 251
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -