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

Jun Zhu, Pamela M. Quizon, Yingying Wang, Charles A. Adeniran, Matthew J. Strauss, Ana C. Jiménez-Torres, Palak Patel, Thomas J. Cirino, Shainnel O. Eans, Haylee R. Hammond, Laure S. Deliscar, Priscilla O'Hara, Surendra K. Saini, Edward Ofori, Rakesh H. Vekariya, Sixue Zhang, Omar Moukha-Chafiq, Theresa H. Nguyen, Subramaniam Ananthan, Corinne E. Augelli-SzafranChang Guo Zhan, Jay P. McLaughlin

Research output: Contribution to journalArticlepeer-review

Abstract

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 [3H]WIN35,428 with hDAT in vitro. SRI-32743 (50 nM) attenuated Tat-induced inhibition of [3H]DA uptake and decreased the cocaine-mediated dissociation of [3H]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.

Original languageEnglish
Article number109239
JournalNeuropharmacology
Volume220
DOIs
StatePublished - Dec 1 2022

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health ( R01DA035714 and R01DA047924 ). All authors have no competing financial interests in relation to the work.

Publisher Copyright:
© 2022 Elsevier Ltd

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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