Tetrabenazine, a vesicular monoamine transporter-2 inhibitor, attenuates morphine-induced hyperlocomotion in mice through alteration of dopamine and 5-hydroxytryptamine turnover in the cerebral cortex.

A single administration with morphine (30 mg/kg, i.p.) induced long-lasting hyperlocomotion in male ICR mice. Pretreatment of mice with a benzoquinolizine derivative tetrabenazine (TBZ; a reversible vesicular monoamine transporter-2 inhibitor) (1 mg/kg, i.p.) for 30 min significantly attenuated the hyperlocomotion induced by morphine, as compared with vehicle (saline)-pretreated mice. No significant change in locomotion was observed in mice pretreated with TBZ (1 mg/kg) alone. Mice treated with TBZ (1 mg/kg) showed an increase in immobility time in a tail suspension test, as compared with saline-treated mice. Pretreatment with TBZ (1 mg/kg) had no effect on morphine (1-30 mg/kg)-induced antinociception. TBZ at a dose of 1 mg/kg inhibited dopamine turnover (the ratio of 3,4-dihydroxyphenylacetic acid/dopamine) and 5-hydroxytryptamine turnover (the ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine) in the cerebral cortex of mice challenged with morphine, as compared with saline-pretreated mice challenged with morphine. No stereotypic behavior was observed in mice treated with morphine (30 mg/kg) in combination with TBZ (1 mg/kg), so the reduction in observed locomotion did not result from induction of stereotypical behavior. Moreover, TBZ (1 and 2 mg/kg) pretreatment had no effect on stereotyped behaviors observed in mice challenged with 10 mg/kg methamphetamine. These data support the potential antagonistic actions of TBZ on some opiate actions, and encourage further exploration of potential effects on morphine reinforcement.