Chronic benzodiazepine administration: IV. Rapid development of tolerance and receptor downregulation associated with alprazolam administration

Abstract

The triazalobenzodiazepine compound alprazolam may have unique clinical effects compared to other benzodiazepines, and both behavioral and neurochemical studies have indicated unusual results after acute doses of alprazolam. To determine the effects of chronic dosage in mice, alprazolam (2 mg/ kg/day) was administered via osmotic pumps for 1–14 days, and open-field activity, plasma and brain concentrations, benzodiazepine receptor binding in vivo and in vitro, [ 35 S]t- butylbicyclophosphorothionate ([ 35S]TBPS) binding, and muscimol-stimulated chloride uptake were determined. Alprazolam decreased motor activity after 1 and 2 days, but tolerance developed by day 4 and persisted to day 14. Plasma and brain concentrations remained constant during the 2-week period. Benzodiazepine receptor binding in vivo was decreased at day 4 compared to day 1 in cortex (CX) and hypothalamus (HYPO), and remained depressed to day 14 in CX but not HYPO. Benzodiazepine binding in vitro and [ 35S]TBPS binding were decreased in CX at day 7. Muscimol-stimulated [ 36Cl −] uptake was decreased at days 4 and 7 compared to day 1, but at day 14 uptake was similar to day 1. These results indicate that behavioral tolerance and receptor downregulation develop rapidly during chronic alprazolam administration. Behavioral and neurochemical changes were similar to those associated with lorazepam administration, but occurred more rapidly and with different regional specificity.