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 GABA(A) receptor. In radioligand binding studies to rat brain membranes, minaxolone caused a 69% increase in [H-3]muscimol binding and a 25% increase in [H-3]flunitrazepam binding and inhibited the binding of [H-3]TBOB with an IC50 of 1 mu M. 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 the 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. (C) 1997 Elsevier Science Inc.