title: Chronic benzodiazepine administration. X. Concurrent administration of the peripheral-type benzodiazepine ligand PK11195 attenuates chronic effects of lorazepam.
abstract: Chronic administration of benzodiazepine active at the tau-aminobutyric acidA receptor ("central" benzodiazepine sites) is associated with behavioral tolerance and receptor downregulation. Recent reports indicate possible interactions between central sites and benzodiazepines active at "peripheral-type" sites located primarily on non-neuronal cells. To evaluate these interactions during chronic administration, we treated mice with lorazepam for 1 to 14 days alone or in combination with the peripheral-type site ligand PK11195 [N-methyl-N-(methyl-1-propyl)chloro-2-phenyl-1-isoquinoline-3-carboxamid e]. Lorazepam was associated with tolerance at 7 days, but tolerance was not observed during concurrent administration of PK11195. Lorazepam was also associated with benzodiazepine receptor down-regulation in cortex and hippocampus at 7 days. With concurrent administration of PK11195, this effect remained in cortex but was absent in hippocampus. tau-Aminobutyric acid-dependent chloride uptake was reduced in both cortex and hippocampus with lorazepam, but not with concurrent lorazepam and PK11195. PK11195 administration alone did not affect behavior or neurochemical parameters, or did it alter brain lorazepam concentrations. These data indicate that concurrent PK11195 administration attenuates behavioral and neurochemical effects of chronic lorazepam administration.
authors.affiliation: Department of Pharmacology, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: L G
authors.initials: LG
authors.lastname: Miller
authors.forename: W R
authors.initials: WR
authors.lastname: Galpern
authors.forename: J J
authors.initials: JJ
authors.lastname: Byrnes
authors.forename: D J
authors.initials: DJ
authors.lastname: Greenblatt
authors.forename: R I
authors.initials: RI
authors.lastname: Shader
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005442:Flumazenil / Q000378:metabolism; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008140:Lorazepam / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D007546:Isoquinolines; D008024:Ligands; D011963:Receptors, GABA-A; D005442:Flumazenil; C037476:tert-butylbicyclophosphorothionate; D008140:Lorazepam; C037850:PK 11195