Chronic administration of methamphetamine downregulates vesicular monoamine transporter2-mediated dopamine dynamics in the nucleus accumbens of inducible HIV-1 Tat transgenic mice

Methamphetamine (METH) use worsens the risk and severity of HIV-1-associated neurocognitive disorders in HIV-infected individuals. Both METH and HIV-1 transactivator of transcription (Tat) protein independently impair dopamine regulation by inhibiting the vesicular monoamine transporter-2 (VMAT2), leading to disrupted dopamine homeostasis and increased neurotoxicity. Using fast scan cyclic voltammetry, this study determined whether in vivo Tat expression and chronic METH exposure alter vesicular dopamine redistribution by measuring baseline dopamine release and depletion of vesicular dopamine induced by the VMAT2 inhibitors Ro4-1284 or GZ-793A in inducible Tat transgenic (iTat-tg) mice. Results revealed that Ro4-1284 and GZ-793A produced concentration-dependent depletion of vesicular dopamine in the nucleus accumbens of C57BL/6J mice. Fourteen days of doxycycline-induced Tat expression, either alone or combined with 7 days of 3 mg/kg METH exposure, significantly decreased baseline dopamine release in iTat-tg mice relative to Tat-null controls. In contrast, METH exposure alone did not significantly alter baseline dopamine release. Additionally, neither Tat nor METH alone changed GZ-793A-mediated dopamine depletion, but co-exposure to Tat and METH significantly accelerated GZ-793A-induced dopamine depletion. These findings demonstrate that Tat and METH downregulate VMAT2-mediated dopamine release, thereby disrupting dopamine homeostasis. Our study highlights VMAT2 as a critical mediator of Tat and METH effects on dopamine dynamics, suggesting that VMAT2 may be an important therapeutic target for developing treatments for methamphetamine use disorder, particularly in people living with HIV-1 infection.