NMDA-receptor antagonism via dextromethorphan and ifenprodil modulates graded anxiety test performance of C57BL/6 mice.
The majority of N-methyl-D-aspartate receptors (NMDA-R) in the adult forebrain are di- or triheteromers composed of NR1, NR2A and NR2B subunits. Subunit non-selective NMDA-R antagonists produce anxiolytic-like effects together with motor and sensory side-effects. The graded anxiety test (GAT), permits the within-task distinction of drug effects on anxiety from those on activity and perception. By testing NMDA-R subunit selective agents in the GAT it might be possible to determine whether their effects on anxiety, activity and perception are interrelated, and whether separate NMDA-R subtypes are involved. Dextromethorphan (weakly NR2A-selective) (10 and 30 mg/kg, i.p.) and ifenprodil (highly NR2B-selective) (1, 3 and 5 mg/kg, i.p.) were tested in the GAT. Both drugs failed to induce anxiolysis devoid of side-effects. However, the 10 mg/kg dose of dextromethorpan showed an anxiolytic, whereas the 30 mg/kg dose showed an anxiogenic, behavioral profile. Since the selective blockade of the NR2B subunit by ifenprodil had no clear anxiolytic effect, the anxiolytic potential of NMDA subunit non-selective agents might involve NR2A-containing receptors.
Dere
E
E
Institute of Physiological Psychology, Center for Biological and Medical Research, University of Düsseldorf, Universitätstrasse 1, 40225 Düsseldorf, Germany. dere@uni-duesseldorf.de
Topic
B
B
De Souza Silva
M A
MA
Fink
H
H
Buddenberg
T
T
Huston
J P
JP
D000818:Animals; D001007:Anxiety / Q000523:psychology*; D001288:Attention / Q000187:drug effects; D003624:Darkness; D003915:Dextromethorphan / Q000494:pharmacology*; D008027:Light; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D010880:Piperidines; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D003915:Dextromethorphan; C010739:ifenprodil