ACUTE AND CHRONIC ANTICONVULSANT EFFECTS OF D(-)CPPENE IN GENETICALLYEPILEPSY-PRONE RATS

Acute administration (0.4-12 mumol/kg, i.p.) of the NMDA antagonist D( -)CPPene (3-(2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid; molec ular weight = 250.2) dose-dependently reduced the incidence of sound-i nduced clonic seizures in genetically epilepsy-prone (GEP) rats. The E D50 value against clonic seizure at + 1 h was 2.6 (2.2-3.2) and at + 4 h was 1.7 (1.3-2.3) mumol/kg (i.p.). Twelve hours after chronic admin istration of an anticonvulsant dose of D(-)CPPene (4 mumol/kg, i.p., t wice daily at 09.00 and 21.00 h, for 14 days), repeat administration o f D(-)CPPene (1.2-12 mumol/kg, i.p.) gave ED50 values against clonic s eizure at + 1 h of 3.4 (2.5-4.8) mumol/kg and at + 4 h of 2.8 (2.0-3.9 ) mumol/kg (i.p.). There was no significant difference observed betwee n ED50 values for these acute and chronic groups. The duration of the anticonvulsant effect observed between + 1 h and + 8 h after D(-)CPPen e (0.4-12 mumol/kg, i.p.) was similar in the acute and chronic groups. The ED50 values for D(-)CPPene-induced impairment of locomotor perfor mance (using a rotarod) at + 3 h were 6.8 (4.4-10.4) and 6.4 (4.1-10.1 ) mumol/kg (i.p.) for the acute and chronic groups respectively. At 7 h after D(-)CPPene administration the ED50 value for locomotor impai rment was 19.5 (10.6-36.0) mumol/kg (i.p.) in the acute group. In this study there is no evidence of tolerance to the anticonvulsant effects and little evidence of tolerance to the adverse effects (ataxia) of D (-)CPPene in GEPRs.