Tolerance to the benzodiazepine diazepam in an animal model of anxiolytic activity.

The antipunishment properties of diazepam (DZP) were investigated in mice treated acutely, or following nine daily treatments with either DZP (5 mg/kg, PO) or its vehicle. Acutely, or following chronic vehicle treatment, DZP produced a dose-related increase in activity punished by footshock. Following chronic DZP, test doses of DZP given 24 or 48 h following the last chronic treatment were no longer, or less effective in enhancing punished activity. Effects on unpunished activity were unaffected. In a study of the time course of tolerance development, tolerance was not seen after one or three daily treatments but was present after 6 days. Following establishment of tolerance by 9 days' treatment, the antipunishment activity of DZP reappeared after 8 days' withdrawal and was restored to acute levels after 16 days. Tolerance was not associated with changes in benzodiazepine (BZ) receptor affinity or numbers, but the ability of GABA to enhance BZ binding was increased. There was no change in the ability of DZP or the convulsant beta-carboline DMCM to modulate 35S-TBPS binding. The mechanism of tolerance to the antipunishment properties of DZP therefore remains unknown.