Tolerance to the anticonvulsant action of benzodiazepines. Relationship to decreased receptor density.

ABSTRACT

Tolerance to the anticonvulsant action of benzodiazepines was studied in rats that had been treated for 4 weeks with 100-150 mg/kg per day of flurazepam. Previous studies had shown that this treatment produced tolerance to motor impairment induced by benzodiazepines and also down-regulation of benzodiazepine receptors in brain, which was seen as a reduced number of binding sites with no change in binding affinity. In the present study, seizures were produced using pentylenetetrazol (PTZ). In rats that had been chronically treated with flurazepam, pretreatment with diazepam was significantly less effective in blocking pentylenetetrazol-induced seizures, thus indicating tolerance. This tolerance could not be explained by a change in sensitivity to pentylenetetrazol resulting from chronic treatment, nor by any differences in levels of active drug in the brain following doses of diazepam. Residual amounts of flurazepam and its active metabolites may have artifactually reduced the apparent degree of tolerance measured 12 hr after the end of chronic treatment, but not at later times. Tolerance to the antipentylenetetrazol action of diazepam was evident up to the fourth day following chronic treatment with flurazepam, but tolerance had largely disappeared a week after chronic treatment. The duration of tolerance was much longer than that reported for tolerance to motor impairment induced by benzodiazepines, and for down-regulation of receptors. These results suggest that different mechanisms or different neural systems must mediate tolerance to these different actions of benzodiazepines. Furthermore, an adaptive reduction in the number of benzodiazepine receptors does not seem to be a likely mechanism for tolerance to the anticonvulsant action of these drugs.