Anti-exploratory effect of N-methyl-D-aspartate in elevated plus-maze. Involvement of NMDA and CCK receptors.
N-Methyl-D-aspartate (NMDA, 20 mg/kg) produced a clear decrease in mouse exploration in open parts of an elevated plus-maze. Paradoxically, 40 mg/kg NMDA did not modify the behavior of the mice in the plus-maze. NMDA at a dose of 80 mg/kg again depressed the exploratory activity of mice, but this effect was accompanied with tremor and compulsive tail biting. The 'anti-exploratory' dose of NMDA (20 mg/kg) increased, whereas the 'tremorigenic' dose (80 mg/kg) significantly decreased the number of cholecystokinin (CCK) binding sites in the mouse cerebral cortex. The competitive NMDA antagonist (+/-)-CPP (2.5-5 mg/kg) and the non-competitive antagonist MK-801 (0.25 mg/kg) antagonized the anti-exploratory effect of NMDA (20 mg/kg). The tricyclic antidepressant imipramine (5 mg/kg, but not 1 or 10 mg/kg) also attenuated the inhibition of exploratory activity induced by NMDA. Of three CCK receptor antagonists tested, the unselective CCK antagonist proglumide (1 mg/kg, but not 0.1 and 10 mg/kg) significantly opposed the anti-exploratory action of NMDA. The selective CCK antagonists L-365,260 (1 microgram/kg) and devazepide (1 microgram/kg) were evidently weaker antagonists of NMDA. Furthermore, 10 micrograms/kg of L-365,260, a CCK-B receptor antagonist, and 1 mg/kg of devazepide, a CCK-A receptor antagonist, even tended to augment the effect of NMDA in the plus-maze. The results of the present study seem to give some support to the notion that not only NMDA receptors, but also CCK-ergic mechanisms are involved in the modulation of anti-exploratory action of NMDA in the elevated plus-maze.
Vasar
E
E
Department of Physiology, Tartu University, Estonia.
Harro
J
J
Lang
A
A
Soosaar
A
A
Oöpik
T
T
Kôks
S
S
Sihver
S
S
Volke
V
V
D000704:Analysis of Variance; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects; D002766:Cholecystokinin / Q000037:antagonists & inhibitors; D020109:Devazepide; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects*; D005260:Female; D007099:Imipramine / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology*; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology; D011377:Proglumide / Q000494:pharmacology; D011869:Radioligand Assay; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects*
D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D010879:Piperazines; D011949:Receptors, Cholecystokinin; D016194:Receptors, N-Methyl-D-Aspartate; C058121:L 365260; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D002766:Cholecystokinin; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D011377:Proglumide; D020109:Devazepide; D007099:Imipramine