Novel Allosteric Modulator Southern Research Institute-32743 Reverses HIV-1 Transactivator of Transcription-Induced Increase in Dopamine Release in the Caudate Putamen of Inducible Transactivator of Transcription Transgenic Mice.

Autor:	Davis SE; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (S.E.D., J.Z.); Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina (M.M.F.); and Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, Alabama (S.A., C.E.A.)., Ferris MJ; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (S.E.D., J.Z.); Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina (M.M.F.); and Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, Alabama (S.A., C.E.A.)., Ananthan S; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (S.E.D., J.Z.); Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina (M.M.F.); and Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, Alabama (S.A., C.E.A.)., Augelli-Szafran CE; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (S.E.D., J.Z.); Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina (M.M.F.); and Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, Alabama (S.A., C.E.A.)., Zhu J; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (S.E.D., J.Z.); Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina (M.M.F.); and Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, Alabama (S.A., C.E.A.) zhuj@cop.sc.edu.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2023 Feb; Vol. 384 (2), pp. 306-314. Date of Electronic Publication: 2022 Dec 01.
DOI:	10.1124/jpet.122.001291
Abstrakt:	Development of neurocognitive disorder in human immunodeficiency virus (HIV)-infected patients has been linked to dysregulation of dopamine by the HIV-1 transactivator of transcription (Tat) protein, a negative allosteric modulator of dopamine transporter (DAT). Using fast scan cyclic voltammetry, the present study determined the effects of in vivo Tat expression on dopamine release in the caudate putamen of inducible Tat transgenic (iTat-tg) mice and the impact of a novel DAT allosteric modulator, Southern Research Institute (SRI)-32743, on the Tat effect. We found that 7- or 14-day doxycycline (Dox)-induced Tat expression in iTat-tg mice resulted in a 2-fold increase in phasic but not tonic stimulated baseline dopamine release relative to saline control mice. To determine whether the Tat-induced increase in dopamine release is mediated by DAT regulation, we examined the effect of an in vitro applied DAT inhibitor, nomifensine, on the dopamine release. Nomifensine (1 nM-10 µ M) concentration-dependently enhanced phasic stimulated dopamine release in both saline- and Dox-treated iTat-tg mice, while the magnitude of the nomifensine-mediated dopamine release was unchanged between saline and Dox treatment groups. A single systemic administration of SRI-32743 prior to animal sacrifice reversed the increased dopamine release in the baseline of phasic dopamine release and nomifensine-augmented dopamine levels in Dox-treated iTat-tg mice, while SRI-32743 alone did not alter baseline of dopamine release. These findings suggest that Tat expression induced an increase in extracellular dopamine levels by not only inhibiting DAT-mediated dopamine transport but also stimulating synaptic dopamine release. Thus, DAT allosteric modulators may serve as a potential therapeutic intervention for HIV infection-dysregulated dopamine system observed in HIV-1 positive individuals. SIGNIFICANCE STATEMENT: HIV infection-induced dysregulation of the dopaminergic system has been implicated in the development of neurocognitive impairments observed in HIV positive patients. Understanding the mechanisms underlying HIV-1 Tat protein-induced alteration of extracellular dopamine levels will provide insights into the development of molecules that can attenuate Tat interaction with targets in the dopaminergic system. Here, we determined whether Tat alters dopamine release and how the novel DAT allosteric modulator, SRI-32743, impacts dopamine neurotransmission to attenuate Tat-induced effects on extracellular dopamine dynamics. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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