ACTION OF GP-47779, THE ACTIVE METABOLITE OF OXCARBAZEPINE, ON THE CORTICOSTRIATAL SYSTEM .1. MODULATION OF CORTICOSTRIATAL SYNAPTIC TRANSMISSION

Oxcarbazepine (OCBZ) is the keto-analogue of carbamazepine (CBZ). In h umans, OCBZ is rapidly and almost completely metabolized to IO, 11-dih ydro-10-hydroxy-CBZ (GP 47779), the main metabolite responsible for th e drug's antiepileptic activity. The corticostriatal pathway is involv ed in the propagation of epileptic discharges. We characterized the el ectrophysiological effects of GP 47779 on striatal neurons by making i ntracellular recordings from corticostriatal slices. GP 47779 (3-100 m u M) produced a dose-dependent inhibition of glutamatergic excitatory postsynaptic potentials (EPSPs). This effect was not coupled either wi th changes of the membrane potential of these cells or with alteration s of their postsynaptic sensitivity to excitatory amino acids (EAA) su ggesting a presynaptic site of action. GP 47779 reduced the current-ev oked firing discharge only at concentrations >100 mu M. GP 47779 did n ot affect the presynaptic inhibitory action of adenosine, showing that presynaptic adenosine receptors were not implicated in the GP 47779-m ediated reduction of corticostriatal EPSPs. Our data indicate that GP 47779 apparently acts directly on corticostriatal terminals to reduce the release of EAA, probably by inhibiting high-voltage-activated (HVA ) calcium (Ca2+) currents (described in the accompanying article). The inhibitory action of GP 47779 on corticostriatal transmission may con tribute to the antiepileptic effects of this drug.