EFFECTS OF SEVERAL BENZODIAZEPINES, ALONE AND IN COMBINATION WITH FLUMAZENIL, IN RHESUS-MONKEYS TRAINED TO DISCRIMINATE PENTOBARBITAL FROM SALINE

The purpose of the present study was to further investigate the relati onship between the DS effects of PB and those of benzodiazepines (BZs) and to begin to collect pharmacological information concerning recept or mechanisms involved in this behavioral effect of BZs. Rhesus monkey s (n=3), trained to discriminate pentobarbital (PB; 10 mg/kg, IG) from saline under a discrete-trials shock avoidance procedure, were given IG diazepam (0.3-10 mg/kg), chlordiazepoxide (1.0-30 mg/kg), or etizol am (0.3-10 mg/kg) alone and in combination with flumazenil (0.01-1.7 m g/kg, IM). Flumazenil was administered 10 min prior to the administrat ion of saline, PB or the BZs. All three BZs fully substituted for PB i n all monkeys. Diazepam was the most potent with a mean ED(50) of 0.81 mg/kg (SEM=0.04) while chlordiazepoxide was the least potent (mean ED (50)=5.78 mg/kg, SEM=1.22 mg/kg). The ED(50) for etizolam was 1.22 mg/ kg (SEM=0.37 mg/kg). Pretreatment with flumazenil (0.01-1.0 mg/kg) res ulted in a dose-related parallel shift to the right in the dose-respon se function for PB-appropriate responding in all monkeys for all three BZs. The mean (n=3) pK(B) value with 0.1 mg/kg flumazenil was 6.51 (S EM=0.42) for diazepam and 6.57 (SEM=0.17) for chlordiazepoxide. This v alue could not be calculated for etizolam because only one monkey was tested with 0.1 mg/kg flumazenil. However, the mean pK(B) for etizolam considering all monkeys and all doses of flumazenil was 6.58 (SEM=0.4 7). Apparent pA(2) values for flumazenil with diazepam were 6.02 for o ne monkey and 7.11 for another. All three BZs tended to increase avera ge latency to respond. Apparent pK(B) and pA(2) analysis may prove use ful for elucidating receptor mechanisms involved in the behavioral eff ects of BZs.