The purpose of the present study was to further investigate the relationship between the DS effects of PB and those of
benzodiazepines (BZs) and to begin to collect pharmacological information concerning receptor mechanisms involved in this behavioral effect of BZs. Rhesus monkeys (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
etizolam (0.3-10 mg/kg) alone and in combination with
flumazenil (0.01-1.7 mg/kg, IM).
Flumazenil was administered 10 min prior to the administration of saline, PB or the BZs. All three BZs fully substituted for PB in all monkeys.
Diazepam was the most potent with a mean ED50 of 0.81 mg/kg (SEM = 0.04) while
chlordiazepoxide was the least potent (mean ED50 = 5.78 mg/kg, SEM = 1.22 mg/kg). The ED50 for
etizolam was 1.22 mg/kg (SEM = 0.37 mg/kg). Pretreatment with
flumazenil (0.01-1.0 mg/kg) resulted in a dose-related parallel shift to the right in the dose-response function for PB-appropriate responding in all monkeys for all three BZs. The mean (n = 3) pKB value with 0.1 mg/kg
flumazenil was 6.51 (SEM = 0.42) for
diazepam and 6.57 (SEM = 0.17) for
chlordiazepoxide. This value could not be calculated for
etizolam because only one monkey was tested with 0.1 mg/kg
flumazenil. However, the mean pKB for
etizolam considering all monkeys and all doses of
flumazenil was 6.58 (SEM = 0.47). Apparent pA2 values for
flumazenil with
diazepam were 6.02 for one monkey and 7.11 for another. All three BZs tended to increase average latency to respond. Apparent pKB and pA2 analysis may prove useful for elucidating receptor mechanisms involved in the behavioral effects of BZs.