Tolerance and Physical Dependence to a Short-Acting

Midazolam is a new ultra short-acting benzodiazepine whose physical dependence properties have not been well character-ized. Our laboratory has demonstrated previously that physical dependence to the long-acting chlordiazepoxide in the rat is inducible by a single intoxicating dose, whereas maximal de-pendence required chronically equivalent maximally tolerable dosing b.i.d. for 5 weeks. Based on the methods developed in our laboratory to quantify benzodiazepine intoxication and with-drawal, Trs were designed to evaluate midazolam’s capacity to induce dependence in the rat after definable acute (1 20 mg/kg p.o.), sub-acute (1 20 mg/kg q.i.d. x 3 days) and chronic (120-1 80 mg/kg bid. x 5 weeks) dosing that was near maximally tolerable. A single dose of midazolam failed to produce with-drawal signs. Tolerance and dependence increased as a functio