Isobolographic analysis of chlordiazepoxide and triazolam combinations in squirrel monkeys discriminating triazolam

Abstract.

Rationale: The discriminative stimulus (DS) effects of chlordiazepoxide (CDP) differ from those of other typical benzodiazepine (BZ) agonists in that CDP does not always occasion full substitution for a BZ agonist DS. Objectives: The present study tested the hypothesis that the unusual DS effects of CDP may result from its relatively low intrinsic efficacy by examining the combinations of CDP and triazolam using isobolographic analysis in squirrel monkeys discriminating triazolam. Methods and results: Squirrel monkeys were previously trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. CDP occasioned partial substitution for triazolam and did not alter the DS effects of triazolam, whereas single doses of triazolam enhanced the DS effects of triazolam, and bretazenil antagonized the triazolam DS. The isobolographic analysis showed that CDP and triazolam combinations resulted in additive effects in animals in which CDP substituted for triazolam, whereas infra-additive effects were obtained in animals in which CDP did not substitute for triazolam. Conclusions: The partial substitution of CDP for triazolam and the infra-additive effects obtained in animals in which CDP did not substitute for triazolam suggest that CDP may have lower intrinsic efficacy than triazolam. However, the lack of overall effect of CDP pretreatment and the lack of shift in animals in which CDP substituted for triazolam suggest that other factors, such as differential activity at BZ receptor subtypes, may play a role in the effects of CDP.