Discriminative stimulus effects of benzodiazepine agonists and partial agonists in pentobarbital-trained rhesus...

The present study examined the relationship between the intrinsic efficacy of benzodiazepines and their ability to reproduce the discriminative stimulus effects of pentobarbital. Rhesus monkeys (n=5) were trained to discriminate pentobarbital (10mg/kg) from saline using a discrete trials shock avoidance procedure (fixed-ratio 5). Drug-appropriate responding and response rate were assessed after intragastric administration of pentobarbital, the high efficacy benzodiazepines triazolam and clonazepam, and the low efficacy benzodiazepines imidazenil and bretazenil. Pentobarbital increased drug-appropriate responding to 100% and decreased the response rate. Triazolam and clonazepam occasioned 80% or greater drug-appropriate responding in four out of four monkeys, and decreased response rate in three out of four monkeys. The antagonist flumazenil decreased drug-appropriate responding and increased response rate after triazolam and clonazepam, consistent with antagonism of the discriminative stimulus and the rate-altering effects of these ligands. Imidazenil occasioned 80% or greater drug-appropriate responding in three out of four monkeys and suppressed the response rate in two out of four monkeys, whereas bretazenil occasioned 80% or greater drug-appropriate responding in two out of four monkeys and decreased the response rate slightly. Bretazenil, when co-administered with a dose of triazolam that produced 90-100% drug-appropriate responding, decreased responding to 0-60% but did not alter the rate-suppressing effects of this ligand. The rank order of potency (based on pmol/kg ED, values) was: triazolam > clonazepam > or = imidazenil > bretazenil. These results demonstrate differences in the pentobarbital-like discriminative stimulus and response rate-decreasing effects among benzodiazepine agonists. Specifically, full agonists engendered pentobarbital-like responding in all subjects with decreased response rates in most subjects, whereas partial agonists engendered pentobarbital-like responding and decreased response rates in subsets of subjects.