Pharmacodynamic and receptor binding changes during chronic lorazepam administration

To assess pharmacodynamic and neurochemical aspects of tolerance, lorazepam (2 mg/kg/day), or vehicle was administered chronically to male Crl: CD-1(I CR)BR mice via implantable osmotic pump. Open-field behavior, benzodiazepin e receptor binding in vitro, receptor autoradiography, and muscimol-stimula ted chloride uptake were examined at both 1 and 14 days. Open-field activit y was depressed in lorazepam-treated animals on Day 1. On Day 14, open-fiel d parameters were indistinguishable from those of vehicle-treated animals, indicating behavioral tolerance. Benzodiazepine binding, as determined by t he specific binding of [I-125]diazepam, was also decreased in cortex on Day 14. Hippocampal binding was unchanged following chronic lorazepam exposure . Apparent affinity in cortical membrane preparations was unchanged, indica ting that altered ligand uptake was due to decreased receptor number. Musci mol-stimulated chloride uptake into cortical synaptoneurosomes from lorazep am-treated animals was not significantly different on Day 1 or Day 14 compa red to vehicle-treated animals. These results confirm that down-regulation of benzodiazepine receptor binding is closely associated with behavioral to lerance to benzodiazepines. These observed changes in binding are not neces sarily associated with robust changes in receptor function. (C) 2001 Elsevi er Science Inc. All rights reserved.