Accelerated benzodiazepine receptor recovery after lorazepam discontinuation

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 t 1/2 for LRZ 19.1 h, and for vehicle, 30.8 h ( P < 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 t 1/2 associated with lorazepam discontinuation is consistent with the observed increase in benzodiazepine receptors in this setting.—Miller, L. G.; Lumpkin, M.; Greenblatt, D. J.; Shader, R. I. Accelerated benzodiazepine receptor recovery after lorazepam discontinuation. FASEB J. 5: 93–97; 1991.