The anxiolytic CRF1 antagonist DMP696 fails to function as a discriminative stimulus and does not substitute for chlordiazepoxide in rats

Rationale: Compounds with a mechanism of action different from benzodiazepines may retain the anxiolytic effects of benzodiazepines with fewer side effects. CRF1 antagonists have anxiolytic-like effects but may have different discriminative stimulus (DS) effects compared with benzodiazepines. Objective: The present study evaluated the similarity of DS effects of a CRF1 antagonist DMP696 to the benzodiazepine chlordiazepoxide and the ability of DMP696 to produce DS effects on its own using drug discrimination procedures, as well as its anxiolytic-like effects after acute or chronic administration. Methods: Rats were trained to discriminate chlordiazepoxide (5.0 mg/kg, IP, 30 min prior to session) from vehicle under a fixed-ratio 10 schedule of food reinforcement and drug- or vehicle-lever selection following administration of DMP696 was determined. The effects of DMP696 on latency to exit a dark chamber (defensive withdrawal model of anxiety) were used as an index of anxiolytic-like activity. Results: In chlordiazepoxide-trained rats, DMP696 (1.0-100 mg/kg, PO) resulted in most of the animals selecting the vehicle lever, as did another anxiolytic, the 5-HT1A partial agonist buspirone (0.3-10 mg/kg, IP). DMP696 reduced exit latency in defensive withdrawal at 10 mg/kg administered either acutely or chronically for 14 days. Thus, the doses of DMP696 studied in drug discrimination were up to 10-fold higher than those active in the anxiety model. In addition, DMP696 (10-60 mg/kg, PO) could not be established as a DS under the conditions used in this study. In a subsequent study, chlordiazepoxide was established as a DS in these same animals. Conclusions: Lack of substitution of DMP696 for the chlordiazepoxide DS in rats and its inability to acquire DS properties suggest that the DS effects of DMP696 differ from those of benzodiazepines.