DEVELOPMENT OF TOLERANCE TO THE ANTICONVULSANT EFFECT OF VALPROATE BUT NOT TO ETHOSUXIMIDE IN A RAT MODEL OF ABSENCE EPILEPSY

Ethosuximide and valproic acid were tested for 4 and 2 weeks, respectively, in rats showing the spontaneous spike-wave syndrome. Ethosuximide suppressed the syndrome at plasma concentrations of 75-100 μg/ml. High doses of valproate (170 mg/kg i.p., t.i.d.), resulting in plasma concentrations of about 500 μg/ml, were necessary to suppress the syndrome, but signs of tolerance to the drug developed from day 5. Tolerance was confined to the number of spike-wave complexes, whereas the duration of the discharges was shortened to 60% of the control value, without there being signs of tolerance. It is assumed that increases in cerebral GABA, induced by the high concentration of valproate, counteracted the anti-absence effect of the drug in this model. © 1990.