Neuropharmacology of a new potential anxiolytic compound, F 2692, 1-(3'-trifluoromethyl phenyl) 1, 4-dihydro 3-amino 4-oxo 6-methyl pyridazine. 2. Evaluation of its tolerance and dependence producing potential and of its effects on benzodiazepine withdrawal in the elevated plus-maze test in rats.
After 21 days administration, diazepam (0.3-3 mg/kg/day) exhibited, 30 min after the last injection, tolerance to the sedative effect and "anxiolytic" activity as recorded in the elevated plus-maze test in rats. A dose-dependent increase of "anxiety" was also observed 24 h after withdrawal from 21 or 90 days of diazepam treatment. In contrast, under the same experimental conditions, F 2692 [1-(3'-trifluoromethyl phenyl) 1,4-dihydro 3-amino 4-oxo 6-methyl pyridazine] (3-30 mg/kg/day) exhibited no tolerance to either the sedative effect or the "anxiolytic" activity and showed no "anxiogenic rebound" response after withdrawal. Chronic diazepam pretreatment for 21 days modified neither the sedative effect nor the dose-dependent "anxiolytic" effect of F 2692. Furthermore, F 2692 could reverse the anxiogenic response after withdrawal from 21 days administration of diazepam. Finally, administration of diazepam for 3 weeks followed by a daily administration of F 2692 for a week induced no increase of "anxiety" 24 h after withdrawal.
Chopin
P
P
Centre de Recherche Pierre Fabre, Castres, France.
Assié
M B
MB
Briley
M
M
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003975:Diazepam / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005106:Exploratory Behavior / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000523:psychology*; D019966:Substance-Related Disorders / Q000523:psychology*
D014151:Anti-Anxiety Agents; D011724:Pyridazines; C077138:F 2692; D003975:Diazepam