Effects of tetrabenazine on methamphetamine-induced hyperactivity in mice are dependent on order and time-course of administration.

The ambulation-increasing effect of methamphetamine (MAP: 2 mg/kg s.c.) in mice persisted for about 3 h. Tetrabenazine (TBZ: 4 mg/kg s.c.), a depleter of monoamines from the cytoplasmic pool did not increase ambulation on its own. Pretreatment with TBZ at 1.5 h before administration of MAP inhibited the stimulant effect of MAP. In contrast, combined administration of two drugs resulted in a transient but considerable enhancement of MAPs stimulant effect. Post-MAP treatment with TBZ at 0.5-2 h hardly modified MAPs behavioral effects. In contrast, 3-6 h post-MAP treatment with TBZ induced a transient increase in activity, although the stimulant effect of MAP had already disappeared. The maximum increase in ambulatory stimulation was produced by 4-h post-MAP treatment with TBZ. The inhibitory effect of TBZ pretreatment on MAP-induced hyperactivity, as well as the transient hyperactivity elicited by TBZ when administered along with MAP, or 4 h after MAP, was dose-dependent. Preliminary studies revealed that transient hyperactivity was never produced by combination of GBR-12909 (a selective dopamine reuptake inhibitor) with TBZ or MAP with oxypertine (a selective norepinephrine releaser/depleter), but produced by combination of nialamide (a monoamine oxidase inhibitor) with TBZ. Inhibition of MAPs effects by TBZ pretreatment suggests that enhancement of dopamine release from cytoplasmic pool, and inhibition of dopamine reuptake by MAP, are involved in MAPs acute behavioral effects. Further, the fact that neither TBZ administration following GBR-12909 pretreatment, nor oxypertine treatment following MAP pretreatment, elicited transient hyperactivity suggests that dopamine is involved in hyperactivity elicited by post-MAP treatment with TBZ. It is also suggested that inhibition of monoamine oxidase (MAO) by MAP and dopamine displacement by TBZ may be responsible for the transient stimulation produced by 3-6 h post-MAP treatment with TBZ. It is hypothesized that the MAO inhibitory action of MAP persists after cessation of its acute stimulant effect, possibly up to 6 h after administration.