Chronic benzodiazepine administration. XI. Concurrent administration of PK11195 attenuates lorazepam discontinuation...

Benzodiazepine discontinuation is associated with alterations in motor activity and gamma-aminobutyric acid-A receptor upregulation in a mouse model. Prior studies indicate that concurrent administration of the compound N-methyl-N-(methyl-1-propyl)chloro-2-phenyl-1-isoquinoline-3- carboxamide (PK1195), a "peripheral" site benzodiazepine antagonist, can attenuate the effects of lorazepam on tolerance and receptor alterations. To evaluate the effects of PK11195 administration on benzodiazepine discontinuation, we administered lorazepam (2 mg/kg per day), PK 11195 (1 to 10 mg/kg per day) or the combination to mice for 7 days, and then evaluated pentylenetetrazole-induced seizure threshold and benzodiazepine binding at days 1, 4, and 7 after discontinuation. Seizure threshold was reduced at 4 days after lorazepam discontinuation; this effect was attenuated by coadministration of PK11195 at 5 mg/kg per day. Lorazepam discontinuation effects were not altered by PK11195 at 1 mg/kg per day, whereas the 10-mg/kg dose was not different from 5 mg/kg per day. The competitive ligand Ro5-4864 at 10 mg/kg per day, blocked the effects of PK11195 on lorazepam discontinuation. Benzodiazepine receptor binding in vivo was increased in the cortex and hippocampus at 4 days postlorazepam discontinuation. This effect was attenuated in the hippocampus but not in the cortex by concurrent administration of PK1195. These data indicate that concurrent administration of PK11195 may attenuate discontinuation effects of lorazepam.