Methamphetamine (METH) disrupts dopamine (DA) homeostasis through interactions with the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). This study examined METH transport, retention, and DA release mechanisms using HEK‑293 cells expressing human DAT alone or with VMAT2. Cells coexpressing VMAT2 exhibited enhanced DA uptake and retention, effects abolished by VMAT2 inhibition, while METH was poorly retained regardless of VMAT2 expression. Pharmacological and pH‑manipulation studies indicated DAT‑dependent DA release mechanisms independent of METH uptake. These findings clarify complementary roles of DAT and VMAT2 in METH‑induced dopaminergic dysregulation.
