Recovery from lorazepam tolerance and the effects of a benzodiazepine antagonist (RO 15-1788) on the development of tolerance.
After 3 days of dosing rats with lorazepam (0.25 mg/kg), tolerance developed to its sedative effects. Recovery from this tolerance was rapid. No differences could be detected in undrugged behaviour 24 h after the last dose and no differences in response to a probe injection could be found when 2 drug-free days intervened between the chronic treatment and test dose. RO 15-1788 (1-4 mg/kg) antagonised the sedative effects of acute lorazepam (0.5 and 0.25 mg/kg), but chronic treatment with these doses concomitantly with lorazepam did not prevent the development of tolerance. However, 4 mg/kg RO 15-1788 administered for 5 days at the same time as lorazepam (0.5 mg/kg) and again 45 min later attenuated the development of tolerance. Plasma concentrations after acute and chronic treatment did not differ for 0.25 mg/kg lorazepam, but they were lower following chronic treatment with 0.5 mg/kg. Therefore the development of behavioural tolerance in rats to the sedative effects of benzodiazepines probably involves changes in benzodiazepine receptors, in addition to a pharmacokinetic contribution after treatment with high doses.
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D004361:Drug Tolerance; D005106:Exploratory Behavior / Q000187:drug effects; D005442:Flumazenil; D008140:Lorazepam / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D005442:Flumazenil; D008140:Lorazepam