CHRONIC BENZODIAZEPINE ADMINISTRATION .11. CONCURRENT ADMINISTRATION OF PK11195 ATTENUATES LORAZEPAM DISCONTINUATION EFFECTS

Benzodiazepine discontinuation is associated with alterations in motor activity and gamma-aminobutyric acid-A receptor upregulation in a mou se model. Prior studies indicate that concurrent administration of the compound ropyl)chloro-2-phenyl-1-isoquinoline-3-carboxamide (PK1195), a ''peripheral'' site benzodiazepine antagonist, can attenuate the ef fects of lorazepam on tolerance and receptor alterations. To evaluate the effects of PK11195 administration on benzodiazepine discontinuatio n, we administered lorazepam (2 mg/kg per day), PK11195 (1 to 10 mg/kg per day) or the combination to mice for 7 days, and then evaluated pe ntylenetetrazole-induced seizure threshold and benzodiazepine binding at days 1, 4, and 7 after discontinuation. Seizure theshold was reduce d at 4 days after lorazepam discontinuation; this effect was attenuate d by coadministration of PK11195 at 5 mg/kg per day. Lorazepam discont inuation effects were not altered by PK11195 at 1 mg/kg per day, where as the 10-mg/kg dose was not different from 5 mg/kg per day. The compe titive ligand Ro5-4864 at 10 mg/kg per day, blocked the effects of PK1 1195 on lorazepam discontinuation. Benzodiazepine receptor binding in vivo was increased in the cortex and hippocampus at 4 days postlorazep am discontinuation. This effect was attenuated in the hippocampus but not in the cortex by concurrent administration of PK1195. These data i ndicate that concurrent administration of PK11195 may attenuate discon tinuation effects of lorazepam.