Development of tolerance to anxiolytic effects of chlordiazepoxide in elevated plus-maze test and decrease of GABAA receptors.
Repeated administration of benzodiazepines has been reported to produce tolerance in animals and humans. Using an elevated plus-maze test and an autoradiographic technique, we investigated whether repeated administration of chlordiazepoxide produced tolerance to its anxiolytic effects, and whether such repeated administration altered benzodiazepine and GABAA receptors. Tolerance to the anxiolytic effect of chlordiazepoxide was produced when it was administered at a dose of 30 mg/kg (i.p.) once a day for 10 and 14 days. In the quantitative autoradiographical study, although repeated chlordiazepoxide treatment had no effect on [3H]flunitrazepam and [3H]Ro 15-4513 binding to benzodiazepine receptors, such treatment reduced [3H]muscimol binding to GABAA receptors in the cortex, caudate putamen, and hippocampus. These results suggest firstly, the production of tolerance to the anxiolytic effects of chlordiazepoxide, and, secondly, that this tolerance may be due to the down-regulation of GABAA receptors, but not of benzodiazepine receptors.
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Japan.
S
S
Ishihara
M
M
Hiramatsu
T
T
Kameyama
T
T
Nabeshima
D000818:Animals; D001386:Azides / Q000378:metabolism; D001569:Benzodiazepines / Q000378:metabolism; D001667:Binding, Competitive; D001923:Brain Chemistry; D002707:Chlordiazepoxide / Q000008:administration & dosage / Q000032:analysis / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004361:Drug Tolerance; D005106:Exploratory Behavior / Q000187:drug effects*; D005445:Flunitrazepam / Q000378:metabolism; D008297:Male; D051379:Mice; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D001386:Azides; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005445:Flunitrazepam; D002707:Chlordiazepoxide; C042957:Ro 15-4513