Tolerance during chronic benzodiazepine treatment associated with decreased receptor binding.

Studies were performed to evaluate the time course and possible significance of changes in specific benzodiazepine binding that occur chronic treatment. Rats were offered flurazepam in a saccharin solution as their only fluid supply. Each rats consumed 100-150 mg/kg daily. Such treatment produced no change in the binding constant (KD) of specific [3H]flunitrazepam binding. Maximal binding capacity (Bmax) was reduced by about 20% after 4 or 8 weeks of treatment, but not by 2 weeks or less. Bmax returned to control within 24 h after the end of chronic treatment. Rats were tested for susceptibility to flurazepam by injecting 20-200 mg/kg i.p., and assessing locomotor impairment. Dose-response analysis showed tolerance only after treatments and at times when Bmax was reduced. The results suggest that the reduced Bmax is an adaptive change in response to chronic benzodiazepine treatment, and that the mechanism for tolerance is a reduction of receptors.