Impact of HIV-1 tat protein on methamphetamine-induced inhibition of vesicular monoamine transporter2-mediated dopamine transport and methamphetamine conditioned place preference in HIV-1 tat transgenic mice

• Published in: European journal of pharmacology 2024-12, Vol.984, p.177030, Article 177030
• Main Authors: Zhu, Jun, Cirincione, Abagail B., Strauss, Matthew J., Davis, Sarah E., Eans, Shainnel O., Tribbitt, Danielle K., Alshakhshir, Nadine, McLaughlin, Jay P.
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport - drug effects; Conditioned place preference; Conditioning, Psychological - drug effects; Dopamine; Dopamine - metabolism; HIV-1 - drug effects; HIV-1 tat protein; Male; Methamphetamine; Methamphetamine - pharmacology; Mice; Mice, Inbred C57BL; Mice, Transgenic; tat Gene Products, Human Immunodeficiency Virus - genetics; Tetrabenazine; Uptake; Vesicular monoamine transpoorter2; Vesicular Monoamine Transport Proteins - genetics; Vesicular Monoamine Transport Proteins - metabolism
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2024.177030

Perturbation of dopamine transmission has been implicated as a contributing factor in HIV-1 associated neurocognitive disorders with concurrent methamphetamine (METH) abuse. We have demonstrated that the HIV-1 protein, transactivator of transcription (Tat), decreases dopamine transport through inhibition of vesicular monoamine transporter2 (VMAT2). This study determined the effects of Tat protein on METH-inhibited VMAT2 function and METH-conditioned place preference (CPP). In vitro exposure of isolated mouse whole brain vesicles to recombinant Tat1-86 or METH displayed a concentration-dependent inhibition of the vesicular [3H]Dopamine uptake, in which a combination of Tat and METH induced a greater reduction of dopamine uptake compared to Tat or METH alone. In vivo, the maximal velocity (Vmax) of vesicular [3H]Dopamine uptake was decreased in inducible Tat transgenic (iTat-tg) mice harvested after treatment with either 21-day doxycycline (Dox) or 14-day METH (3 mg/kg, i.p., daily), whereas these mice treated with both Dox and METH displayed an additive reduction of the Vmax compared to either Tat or METH alone. Moreover, Dox-induced Tat expression increased METH-CPP in an exposure-dependent manner, with iTat-tg mice demonstrating a 2.3-fold potentiation of METH-CPP compared with Tat null control mice upon administration of Dox for 14 days. Furthermore, a 7-day administration of Dox reinstated extinguished METH-CPP. Collectively, these results suggest a synergistic effect of Tat protein and METH on inhibition of VMAT2-mediated DA transport, potentially contributing to potentiation of METH-CPP in iTat-tg mice. •In vitro, combined Tat and METH induces a synergistic inhibitory effect on VMAT2-mediated DA uptake.•In vivo, Tat expression reduces the potency of tetrabenazine inhibiting VMAT2-mediated DA uptake.•In vivo, combined Tat and METH displays a great reduction of DA uptake via VMAT2, compared to Tat or METH alone.•In vivo, Tat expression in iTat-tg mice displays a potentiation of METH-CPP and reinstates extinguished METH-CPP. [Display omitted]