Development of tolerance in mice to the sedative effects of the neuroactive steroid minaxolone following chronic exposure.
Minaxolone is a potent ligand for the neurosteroid binding site of the GABAA, receptor. In radioligand binding studies to rat brain membranes, minaxolone caused a 69% increase in [3H]muscimol binding and a 25% increase in [3H]flunitrazepam binding and inhibited the binding of [3H]TBOB with an IC50 of 1 microM. In mice, minaxolone (100 mg/kg, orally) had marked sedative effects as indicated by a reduction in locomotor activity. Chronic dosing with minaxolone (100 mg/kg, orally, once daily for 7 days) resulted in a loss of sedative response to an acute dose of the drug, indicating development of tolerance. Chronic dosing with temazepam (10 mg/kg, orally, once daily for 7 days) resulted in the development of tolerance to an acute dose of temazepam; however, the two drugs did not appear to be cross-tolerant, indicating that they may have a different mechanism of action at the level of the GABAA receptor.
Marshall
F H
FH
Cellular Sciences Division, Glaxo Wellcome Medicines Research Centre, Stevenage, Hertfordshire, UK.
Stratton
S C
SC
Mullings
J
J
Ford
E
E
Worton
S P
SP
Oakley
N R
NR
Hagan
R M
RM
D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005445:Flunitrazepam / Q000378:metabolism / Q000494:pharmacology; D018755:GABA Agonists / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009118:Muscimol / Q000378:metabolism; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D013693:Temazepam / Q000378:metabolism / Q000494:pharmacology
D000777:Anesthetics; D018755:GABA Agonists; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D009118:Muscimol; D005445:Flunitrazepam; C020413:minaxolone; D011280:Pregnanolone; D013693:Temazepam