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 [ 3H]muscimol binding and a 25% increase in [ 3H]flunitrazepam binding and inhibited the binding of [ 3H]TBOB with an IC 50 of 1 μM. 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 GABA A receptor.