BLOCKADE OF BEHAVIORAL-EFFECTS OF BRETAZENIL BY FLUMAZENIL AND ZK-93,426 IN PIGEONS

Benzodiazepine receptor partial agonists manifest full efficacy in pre clinical tests of anxiolytic drug action but do not fully reproduce th e discriminative stimulus effects of benzodiazepine receptor full agon ists in pigeons. The partial agonist, bretazenil, binds to both diazep am-sensitive and diazepam-insensitive GABA(A) receptors. Previous stud ies have suggested a role for each of these receptor populations in so me behavioral effects of bretazenil in pigeons. A possible role for th ese receptor subtypes in the behavioral effects of bretazenil was furt her investigated through drug interaction studies with the benzodiazep ine receptor antagonists, flumazenil and ZK 93,426. Whereas flumazenil binds with high affinity to both receptor isoforms, ZK 93,426 binds p referentially to diazepam-sensitive binding sites. Bretazenil markedly increased punished responding of pigeons without significantly affect ing nonpunished responding. In pigeons discriminating the full benzodi azepine receptor agonist, midazolam, from saline, bretazenil produced only 60-75% maximal effect. Flumazenil and ZK 93,426 neither increased punished responding nor substituted for midazolam, but hose-dependent ly blocked the effects of bretazenil on punished responding. Flumazeni l also dose-dependently blocked the effects of bretazenil in midazolam -discriminating pigeons, whereas ZK 93,426 only attenuated this effect . These results indicate that bretazenil's actions as a partial agonis t at diazepam-sensitive benzodiazepine receptors mediate increases in unished responding and substitution for the discriminiative stimulus e ffects of midazolam in pigeons. The differences in the effects of flum azenil and ZK 93,426 on the discriminative stimulus effects of bretaze nil suggest a potential contribution of diazepam-insensitive sites to this behavioral effect. Copyright (C) 1997 Elsevier Science Inc.