Clonazepam-induced hyperphagia in nondeprived rats: tests of pharmacological specificity with Ro5-4864, Ro5-3663, Ro15-1788 and CGS 9896.
Nondeprived male rats were familiarised with daily 60 min access to a highly palatable diet, consisting of powdered rat diet, sweetened condensed milk and water. Clonazepam (0.625-5.0 mg/kg, IP) produced a substantial increase in food consumption within the first 30 min of access. The increase was similar across all dose conditions, suggesting that a maximal effect may have been achieved with a dose as small as 0.625 mg/kg. The hyperphagia induced by clonazepam was reversed by the benzodiazepine receptor antagonist, Ro15-1788 (5.0-20.0 mg/kg), indicating that the effect was benzodiazepine receptor-mediated. Treatments with the peripheral-type benzodiazepine agonist, Ro5-4864, did not induce a hyperphagic response. Instead, food consumption was significantly depressed following the administration of Ro5-4864 at 20 and 40 mg/kg, IP. A comparison of the clonazepam and Ro5-4864 data suggests that benzodiazepine-induced hyperphagia is mediated by central-type benzodiazepine binding sites. The pyrazoloquinoline, CGS 9896, binds with high affinity to benzodiazepine sites and has recently been described as a nonsedating anxiolytic. CGS 9896 (2.5-20.0 mg/kg, administered either IP or PO) did not affect consumption of the highly palatable diet. In consequence, anxiolytic and hyperphagic effects of drug actions at benzodiazepine receptors may be dissociated in the case of this compound. The atypical 1,4-benzodiazepine, Ro5-3663, a GABA antagonist which may act at the picrotoxinin site, produced a dose-related reduction in food consumption. Comparison with the results for Ro5-4864 rules out an interpretation for the anorexia in terms of anxiogenic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Cooper
S J
SJ
Gilbert
D B
DB
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002998:Clonazepam / Q000494:pharmacology*; D004347:Drug Interactions; D005247:Feeding Behavior / Q000187:drug effects*; D005442:Flumazenil; D006801:Humans; D006963:Hyperphagia / Q000139:chemically induced; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000494:pharmacology
D001570:Benzodiazepinones; D011720:Pyrazoles; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; D005442:Flumazenil; D002998:Clonazepam; C022193:Ro 5-3663; C034704:2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one