Methamphetamine-induced locomotor activity and sensitization in dopamine transporter and vesicular monoamine transporter 2 double mutant mice

Rationale: The dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) play pivotal roles in the action of methamphetamine (MAP), including acute locomotor effects and behavioral sensitization. However, the relative impact of heterozygous DAT and VMAT2 knockouts (KOs) on the behavioral effects of MAP remains unknown. Objectives: To evaluate the roles of DAT and VMAT2 in MAP-induced locomotor behavior, we examined locomotor activity and sensitization in heterozygous DAT KO (DAT+/-), heterozygous VMAT2 KO (VMAT2+/-), double heterozygous DAT/VMAT2 KO (DAT+/-VMAT2+/-), and wild-type (WT) mice. Results: Acute 1 mg/kg MAP injection induced significant locomotor increases in WT and VMAT2+/- mice but not in DAT+/- and DAT+/-VMAT2+/- mice. Acute 2 mg/kg MAP significantly increased locomotor activity in all genotypes. Repeated 1 mg/kg MAP injections revealed a delayed and attenuated development of sensitization in DAT+/- and DAT+/-VMAT2+/- mice compared to WT mice and delayed development in VMAT2+/- mice. In repeated 2 mg/kg MAP injections, DAT+/- and DAT+/-VMAT2+/- mice showed delayed but not attenuated development of sensitization, while there was no difference in the onset of sensitization between VMAT2+/- and WT mice. In DAT+/-VMAT2+/- mice, all of MAP-induced behavioral responses were similar to those in DAT+/- but not VMAT2+/- mice. Conclusions: Heterozygous deletion of DAT attenuates the locomotor effects of MAP and may play larger role in behavioral responses to MAP compared to heterozygous deletion of VMAT2.