DISCRIMINATIVE STIMULUS EFFECTS OF THE BENZODIAZEPINE RECEPTOR PARTIAL AGONIST BRETAZENIL IN PIGEONS AND IN RATS

Bretazenil is a partial agonist at diazepam-sensitive (DS) GABA(A) rec eptors, and it also binds with high affinity to diazepam-insensitive ( DI) GABA(A) receptors. A unique discriminative stimulus effect transdu ced by binding at DI benzodiazepine (BZ) receptors has been reported i n pigeons, but has not been established in rats. Further, differences have been observed between rats and pigeons in results of drug discrim ination experiments utilizing BZ receptor partial agonists. Therefore, to examine the discriminative stimulus effects of bretazenil and to e xplore the possibility of species differences in substitution profiles , pigeons and rats were trained to discriminate 0.3 mg/kg bretazenil f rom vehicle. Flumazenil (0.03-1.0 mg/kg) did not substitute for bretaz enil in pigeons, despite full substitution of bretazenil for flumazeni l in this species. Flumazenil (0.03-10.0 mg/kg) also did not substitut e for bretazenil in rats, despite the partial agonist effects of fluma zenil in rats. Likewise, midazolam (0.3-1.0 mg/kg) did not substitute for bretazenil in pigeons, despite the fact that bretazenil partially substitutes for midazolam in pigeons. However in rats, midazolam produ ced full, dose-dependent substitution (0.03-3.2 mg/kg). Differences ma y result from different fractional receptor occupancy requirements for the mediation of discriminative stimulus effects through DS BZ recept ors, and/or from a contribution of DI BZ receptor binding in pigeons.