Influence of memantine on brain monoaminergic neurotransmission parameters in mice: neurochemical and behavioral study.

Memantine, a non-competitive antagonist of NMDA receptors, has recently been used in Alzheimer's disease. The influences of memantine on behavioral changes, monoamine oxidase (MAO) activity and reuptake of both serotonin (5-HT) and dopamine in mice were examined in the present study. Memantine dose-dependently increased locomotor activity. This effect was inhibited by intraperitoneal (i.p.) administration of haloperidol. Furthermore, administration [intracerebroventricular (i.c.v.)] of memantine did not induce the head-twitch response (HTR). However, the 5-HT-induced HTR was potentiated by the combined administration of memantine. The enhanced HTR was inhibited by i.p. administration of haloperidol or 5-HT(2A) antagonist ketanserin. Memantine at 1 mM inhibited both MAO-A and MAO-B activities in mouse forebrain homogenates to 37% and 64% of controls, respectively. Lineweaver-Burk plots analysis revealed competitive inhibition with both MAO-A and MAO-B. The inhibitions were also reversible. Memantine inhibited the reuptake of both 5-HT and dopamine into mouse forebrain synaptosomes. 5-HT and dopamine reuptakes were inhibited to 2% and 16% of controls, respectively, with 1 mM memantine. These findings suggest that the increased locomotor activity and enhanced 5-HT-induced HTR by memantine may result from the reuptake and turnover inhibitions of 5-HT and dopamine.