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(ICR)BR mice via implantable osmotic pump. Open-field behavior, benzodiazepine receptor binding in vitro, receptor autoradiography, and muscimol-stimulated chloride uptake were examined at both 1 and 14 days. Open-field activity was depressed in lorazepam-treated animals on Day 1. On Day 14, open-field parameters were indistinguishable from those of vehicle-treated animals, indicating behavioral tolerance. Benzodiazepine binding, as determined by the specific binding of [125I]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, indicating that altered ligand uptake was due to decreased receptor number. Muscimol-stimulated chloride uptake into cortical synaptoneurosomes from lorazepam-treated animals was not significantly different on Day 1 or Day 14 compared to vehicle-treated animals. These results confirm that down-regulation of benzodiazepine receptor binding is closely associated with behavioral tolerance to benzodiazepines. These observed changes in binding are not necessarily associated with robust changes in receptor function.
Fahey
J M
JM
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
Pritchard
G A
GA
Grassi
J M
JM
Pratt
J S
JS
Shader
R I
RI
Greenblatt
D J
DJ
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D005445:Flunitrazepam / Q000493:pharmacokinetics; D018755:GABA Agonists / Q000494:pharmacology; D008140:Lorazepam / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009118:Muscimol / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*
D014151:Anti-Anxiety Agents; D002712:Chlorides; D018755:GABA Agonists; D011963:Receptors, GABA-A; D009118:Muscimol; D005445:Flunitrazepam; D008140:Lorazepam; D003975:Diazepam