The anxiolytic CRF(1) antagonist DMP696 fails to function as a discriminative stimulus and does not substitute for chlordiazepoxide in rats.
BACKGROUND
Compounds with a mechanism of action different from benzodiazepines may retain the anxiolytic effects of benzodiazepines with fewer side effects. CRF(1) 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 CRF(1) 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-HT(1A) 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.
Lelas
Snjezana
S
Central Nervous System Diseases Research, Bristol-Myers Squibb Company, Route 141 and Henry Clay Roads, Experimental Station E400/4418, Wilmington, DE 19880-0400, USA. snjezana.lelas@bms.com
Zeller
Kim L
KL
Ward
Kathryn A
KA
McElroy
John F
JF
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002707:Chlordiazepoxide / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
D014151:Anti-Anxiety Agents; C404928:DMP 696; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D000099052:CRF Receptor, Type 1; D002707:Chlordiazepoxide