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.
Department of Pharmacology, Tohoku Pharmaceutical University, Sendai, Japan.
Hiroshi
H
Onogi
Seiichiro
S
Ishigaki
Osamu
O
Nakagawasai
Yumiko
Y
Arai-Kato
Yuichiro
Y
Arai
Hiromi
H
Watanabe
Atsushi
A
Miyamoto
Koichi
K
Tan-no
Takeshi
T
Tadano
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008995:Monoamine Oxidase / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects*; D016548:Prosencephalon / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*
D000978:Antiparkinson Agents; D012701:Serotonin; D008995:Monoamine Oxidase; D006220:Haloperidol; D004298:Dopamine; D008559:Memantine