Tolerance to diazepam-induced motor impairment: a study with GABAA receptor alpha6 subunit knockout mice.
Development of tolerance to motor-impairing effects of repeated administration of moderate diazepam doses (5.0-7.5 mg/kg; three times daily PO 3 weeks) was compared between mice deficient in the cerebellar granule cell-restricted GABAA receptor alpha6 subunit and their wild-type controls. The alpha6 -/- mice were more impaired by the initial challenge doses of diazepam (5 or 10 mg/kg) than their controls, but acquired partial tolerance by the second tests with the same doses 4-7 days later. Chronic treatment produced complete tolerance in both mouse lines. Ligand autoradiography revealed a significant reduction in baseline benzodiazepine and chloride channel site-bindings in various regions of the alpha6 -/- brains, but the chronic diazepam treatment did not consistently alter baseline or benzodiazepine site agonist and inverse agonist-modulated binding in the alpha6 -/- and wildtype mice. The results indicate that tolerance to motor-impairing actions of diazepam is independent of the diazepam-insensitive alpha6 subunit-containing receptors, which rules out the possibility that tolerance emerges as an increase in structurally benzodiazepine-insensitive receptor population.
Vekovischeva
Olga
O
Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland.
Uusi-Oukari
Mikko
M
Korpi
Esa R
ER
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D003975:Diazepam / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009422:Nervous System Diseases / Q000503:physiopathology; D009928:Organ Specificity; D011963:Receptors, GABA-A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013462:Sulfur Radioisotopes / Q000493:pharmacokinetics; D014018:Tissue Distribution
D019086:Bridged Bicyclo Compounds, Heterocyclic; C546172:Gabra6 protein, mouse; D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; C037476:tert-butylbicyclophosphorothionate; D003975:Diazepam