PRECIPITATED WITHDRAWAL IN SQUIRREL-MONKEYS AFTER REPEATED DAILY ORAL-ADMINISTRATION OF ALPRAZOLAM, DIAZEPAM, FLUNITRAZEPAM OR OXAZEPAM

The lowest dose of alprazolam, diazepam, flunitrazepam and oxazepam co nsistently to induce loss of righting reflex in squirrel monkeys or ve hicle was orally administered to monkeys on 18 consecutive days: 2 mg/ kg alprazolam (n = 4): 30 mg/kg diazepam (n = 4), 1 mg/kg flunitrazepa m (n = 4), 280 mg/kg oxazepam (n = 5), or vehicle (n = 4). Tolerance d eveloped rapidly for loss of righting reflex, more slowly for sleep an d only minimally for muscle relaxation observed during the period imme diately following daily oral administration. Injection of the specific benzodiazepine receptor antagonist flumazenil (10 mg/kg IV) 5 h after the ninth daily oral treatment produced signs of precipitated withdra wal (tremor, vomiting and/or convulsions) in one alprazolam-, four dia zepam-, one flunitrazepam- and four oxazepam-treated monkeys, but not in the vehicle-treated monkeys. Physiological saline injected intraven ously several days later under these same experimental conditions fail ed to provoke a precipitated withdrawal reaction. When flumazenil-indu ced precipitated withdrawal was again evaluated after the 18th daily o ral treatment, withdrawal signs were observed in all alprazolam- and a ll diazepam-treated monkeys, as well as in three flunitrazepam- and th ree oxazepam-treated monkeys, but not in the vehicle-treated monkeys ( convulsions were observed in one alprazolam-, two diazepam-, one fluni trazepam- and two oxazepam-treated monkeys). No signs of spontaneous w ithdrawal were observed in any of the monkeys during a subsequent 3-we ek drug-free period. Thus, repeated administration of approximately eq uieffective doses of these four benzodiazepines resulted in a similar development of tolerance and physical dependence (indicated by the occ urrence of a precipitated withdrawal reaction).