Tolerance to anticonvulsant effects of the partial benzodiazepine receptor agonist abecarnil in kindled rats involves...

The effects of chronic treatment with the beta-carboline, abecarnil, a novel partial and/or subtype-specific agonist at central benzodiazepine receptors, were studied on fully kindled amygdaloid seizures in rats. Two different experimental protocols were used to differentiate between "pharmacologic tolerance', i.e. tolerance as a function of drug exposure, and "contingent tolerance, i.e. tolerance contingent upon the repeated occurrence of the criterion effect, i.e. the anticonvulsant effect. When kindled seizures were repeatedly initiated during chronic treatment of rats with abecarnil (5 mg/kg i.p. three times daily), marked tolerance developed to its anticonvulsant effect, although plasma levels of abecarnil even increased during the 2 weeks of treatment. When the same treatment protocol was used, but seizures were initiated only at the start and end of the treatment period, almost no tolerance to the anticonvulsant effect of abecarnil was measured, indicating an important role of learning processes for the development of tolerance. In contrast to the differences in anticonvulsant tolerance between the two protocols, the motor impairment induced by abecarnil was similarly attenuated during chronic treatment according to both protocols. The data indicate that, because of the response contingency in abecarnil tolerance, development of tolerance to anticonvulsant effects of this compound depends critically on seizure frequency during drug administration, while adverse effects of this compound are reduced independently of seizure frequency.