SRI-32743, a novel allosteric modulator, attenuates HIV-1 Tat protein-induced inhibition of the dopamine transporter and alleviates the potentiation of cocaine reward in HIV-1 Tat transgenic mice.

Autor: Zhu J; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA. Electronic address: zhuj@cop.sc.edu., Quizon PM; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA., Wang Y; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA., Adeniran CA; Molecular Modeling and Biopharmaceutical Center, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA., Strauss MJ; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA., Jiménez-Torres AC; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA., Patel P; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA., Cirino TJ; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA., Eans SO; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA., Hammond HR; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA., Deliscar LS; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA., O'Hara P; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA., Saini SK; Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA., Ofori E; Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA., Vekariya RH; Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA., Zhang S; Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA., Moukha-Chafiq O; Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA., Nguyen TH; Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA., Ananthan S; Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA., Augelli-Szafran CE; Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA., Zhan CG; Molecular Modeling and Biopharmaceutical Center, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA., McLaughlin JP; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2022 Dec 01; Vol. 220, pp. 109239. Date of Electronic Publication: 2022 Sep 17.
DOI: 10.1016/j.neuropharm.2022.109239
Abstrakt: Cocaine abuse increases the incidence of HIV-1-associated neurocognitive disorders. We have demonstrated that HIV-1 transactivator of transcription (Tat) allosterically modulates dopamine (DA) reuptake through the human DA transporter (hDAT), potentially contributing to Tat-induced cognitive impairment and potentiation of cocaine conditioned place preference (CPP). This study determined the effects of a novel allosteric modulator of DAT, SRI-32743, on the interactions of HIV-1 Tat, DA, cocaine, and [ 3 H]WIN35,428 with hDAT in vitro. SRI-32743 (50 nM) attenuated Tat-induced inhibition of [ 3 H]DA uptake and decreased the cocaine-mediated dissociation of [ 3 H]WIN35,428 binding in CHO cells expressing hDAT, suggesting a SRI-32743-mediated allosteric modulation of the Tat-DAT interaction. In further in vivo studies utilizing doxycycline-inducible Tat transgenic (iTat-tg) mice, 14 days of Tat expression significantly reduced the recognition index by 31.7% in the final phase of novel object recognition (NOR) and potentiated cocaine-CPP 2.7-fold compared to responses of vehicle-treated control iTat-tg mice. The Tat-induced NOR deficits and potentiation of cocaine-CPP were not observed in saline-treated iTat-tg or doxycycline-treated G-tg (Tat-null) mice. Systemic administration (i.p.) of SRI-32743 prior to behavioral testing ameliorated Tat-induced impairment of NOR (at a dose of 10 mg/kg) and the Tat-induced potentiation of cocaine-CPP (at doses of 1 or 10 mg/kg). These findings demonstrate that Tat and cocaine interactions with DAT may be regulated by compounds interacting at the DAT allosteric modulatory sites, suggesting a potential therapeutic intervention for HIV-infected patients with concurrent cocaine abuse.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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