Involvement of N-methyl-D-aspartate (NMDA) receptors in noncompetitive NMDA receptor antagonist-induced hyperlocomotion in mice.
The role of the N-methyl-D-aspartate (NMDA) receptors in hyperlocomotion induced by (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), a potent and selective noncompetitive NMDA receptor antagonist, was examined in male ddY mice. A low dose of MK-801 [0.2 mg/kg, intraperitoneally (IP)] produced a marked increase in locomotor activity without obvious staggering gait. In contrast, a high dose (1 mg/kg, IP) induced a typical motor syndrome characterized by increased locomotor activity, stereotyped behavior, and severe ataxia. NMDA (60-120 mg/kg, IP), an NMDA receptor agonist, dose dependently antagonized hyperlocomotion induced by a low dose of MK-801 (0.2 mg/kg). However, even a high convulsive dose of NMDA (240 mg/kg, IP) could not completely antagonize the hyperactivity induced by MK-801. On the other hand, neither a high dose of N-methyl-L-aspartate (400 mg/kg, IP), a stereoisomer of NMDA, nor a critical subconvulsive dose of kainate (10 mg/kg, IP), a non-NMDA receptor agonist, reversed MK-801-induced hyperlocomotion. The activity induced by MK-801 was potently suppressed by low doses of haloperidol (0.05-0.1 mg/kg, IP), a dopamine (DA) receptor antagonist, in a dose-dependent manner. These data for MK-801 were similar to those for phencyclidine and ketamine, other noncompetitive NMDA receptor antagonists. These results suggest that noncompetitive NMDA receptor antagonist-induced hyperlocomotion is mediated, at least in part, by NMDA receptor antagonism, although this hyperactivity may also involve dopaminergic mechanisms through indirect (perhaps by reducing NMDA receptor-mediated neurotransmission) and/or direct (by inhibiting DA uptake) effects on DA neurons.
Irifune
M
M
Department of Pharmacology, Faculty of Medicine, Kagoshima University, Japan.
Shimizu
T
T
Nomoto
M
M
Fukuda
T
T
D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001667:Binding, Competitive / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects*; D016202:N-Methylaspartate / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012018:Reflex / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects
D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D007649:Ketamine; D016291:Dizocilpine Maleate; D010622:Phencyclidine; D006220:Haloperidol