The FASEB Journal, Vol 5, 93-97, Copyright © 1991 by The Federation of American Societies for Experimental Biology

RESEARCH COMMUNICATIONS

Accelerated benzodiazepine receptor recovery after lorazepam discontinuation

LG Miller, M Lumpkin, DJ Greenblatt and RI Shader
Division of Clinical Pharmacology, Tufts University School of Medicine, Boston, Massachusetts.

Benzodiazepine discontinuation can lead to a behavioral syndrome in animals and humans. In a mouse model, this syndrome is associated with benzodiazepine receptor up-regulation. The protein-modifying reagent, N- ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), has been used to irreversibly inactivate a number of neurotransmitter receptors including benzodiazepine receptors, and thus allows estimation of receptor recovery in vivo. To assess benzodiazepine receptor recovery after benzodiazepine discontinuation, we treated mice with lorazepam (LRZ), 2 mg.kg-1.day-1 for 1 wk. After 24 h, EEDQ (12.5 mg/kg) was administered, and benzodiazepine binding in the cortex and cerebellum was determined after 4-144 h. EEDQ treatment decreased receptor density in the cortex in both LRZ- and vehicle-treated groups by approximately 50%, with no change in apparent affinity as previously reported. Binding in both groups returned to control values after 96 h. Kinetic analysis indicated a more rapid increase in binding in LRZ-compared with vehicle-treated animals, with t1/2 for LRZ 19.1 h, and for vehicle, 30.8 h (P less than 0.05). Receptor density was decreased in the cerebellum after EEDQ by approximately 40% in both treatment groups, with no change in apparent affinity. Receptor density returned to control values at 96 h, with no difference in kinetics in LRZ- compared with vehicle-treated mice. The decrease in receptor t1/2 associated with lorazepam discontinuation is consistent with the observed increase in benzodiazepine receptors in this setting.