Lorazepam and FG 7142 induce tolerance to the DMCM antagonistic effect of benzodiazepine receptor ligands.
Mice were given chronic treatment with lorazepam 10 mg/kg PO or FG 7142 40 mg/kg IP once a day for 14 days. The pretreatments with lorazepam and FG 7142 did not change the sensitivity of the mice to the convulsant effect of DMCM. Lorazepam pretreated mice showed a significantly lower sensitivity to the anticonvulsant effects of the benzodiazepine (BZ) receptor ligands lorazepam, ZK 93423, ZK 91296, Ro 15-1788 and ZK 93426 administered acutely by the IP route when challenged with DMCM 24 hr after the last dose of lorazepam. FG 7142 pretreated mice showed a significantly lower sensitivity to the anticonvulsant effect of the two agonists lorazepam and ZK 93423 and to the antagonist Ro 15-1788, whereas the effects of ZK 91296 and ZK 93426 were left unchanged. The reduced DMCM antagonistic effects of the BZ receptor ligands may indicate that these ligands may either have lost some of their affinity to those BZ receptors being responsible for the DMCM-induced seizures or they may have lost some efficacy in allosterically inhibiting DMCM binding or as a third possibility may have lost efficacy at a BZ receptor site downstream to the seizure-inducing center in the brain.
Petersen
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EN
A/S Ferrosan, Research Division, Copenhagen, Soeborg, Denmark.
Jensen
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LH
D000818:Animals; D002243:Carbolines / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D008140:Lorazepam / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced*
D002243:Carbolines; D011963:Receptors, GABA-A; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; C035874:FG 7142; D008140:Lorazepam