The influence of the benzodiazepine receptor antagonist flumazenil on the anxiolytic-like effects of CGP 37849 and ACPC in rats

In this paper we examined the effect of fIumazenil (Ro 15-1788, 10 mg/kg), a benzodiazepine receptor antagonist, on the anticonflict activity of DL-(E )-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and 1-aminocyclopropanecar boxylic acid (ACPC), a partial agonist at glycine(B) receptors, in the Voge l conflict drinking test in rats. The effect of flumazenil on the anxiolyti c-like (in the plus-maze test) and the anticonvulsant (in the maximal elect roshock-induced seizures) activities of CGP 37849 in rats was also studied. Diazepam was used as a reference drug. CGP 37849 (2.5-5 mg/kg), ACPC (50-2 00 mg/kg) and diazepam (2.5-5 mg/kg) significantly and dose-dependently inc reased the number of shocks accepted during experimental sessions in the co nflict drinking test. Flumazenil partly but significantly reduced the antic onflict effect of CGP 37849, and it fully blocked the anticonflict effect o f ACPC and diazepam. CGP 37849 (2.5-5 mg/kg) and diazepam (2.5-5 mg/kg) wer e also active in the plus-maze test, as they significantly increased the pe rcentage of the time spent in and entries into the open arms of the plus-ma ze, both those effects having been antagonized by flumazenil. Flumazenil al one was inactive in both the conflict drinking and the plus-maze tests. In the maximal electroshock-induced seizures, both CGP 37849 (2.55- 5 mg/kg) a nd diazepam (5-10 mg/kg) produced anticonvulsant effects, of which only tha t of diazepam was antagonized by flumazenil. The results of the present stu dy showing antagonism of flumazenil towards the anxiolytic-like effects of CGP 37849 and ACPC suggest involvement of benzodiazepine receptors in such an activity of the NMDA and glycine(B) receptor ligands, respectively, whic h may be due to a possible interaction between NMDA and GABA/benzodiazepine systems. The lack of effect of the benzodiazepine antagonist on the antico nvulsant activity of CGP 37849 indicates that involvement of benzodiazepine receptors in the pharmacological action of the NMDA antagonist is not a ge neral phenomenon. (C) 2000 Elsevier Science Ltd. Al rights reserved.