Action of GP 47779, the active metabolite of oxcarbazepine, on the corticostriatal system. I. Modulation of corticostriatal synaptic transmission.
Oxcarbazepine (OCBZ) is the keto-analogue of carbamazepine (CBZ). In humans, OCBZ is rapidly and almost completely metabolized to 10, 11-dihydro-10-hydroxy-CBZ (GP 47779), the main metabolite responsible for the drug's antiepileptic activity. The corticostriatal pathway is involved in the propagation of epileptic discharges. We characterized the electrophysiological effects of GP 47779 on striatal neurons by making intracellular recordings from corticostriatal slices. GP 47779 (3-100 microM) produced a dose-dependent inhibition of glutamatergic excitatory postsynaptic potentials (EPSPs). This effect was not coupled either with changes of the membrane potential of these cells or with alterations of their postsynaptic sensitivity to excitatory amino acids (EAA) suggesting a presynaptic site of action. GP 47779 reduced the current-evoked firing discharge only at concentrations > 100 microM. GP 47779 did not affect the presynaptic inhibitory action of adenosine, showing that presynaptic adenosine receptors were not implicated in the GP 47779-mediated 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 contribute to the antiepileptic effects of this drug.
Calabresi
P
P
Dipartimento di Sanità, Università Tor Vergata, Rome, Italy.
De Murtas
M
M
Stefani
A
A
Pisani
A
A
Sancesario
G
G
Mercuri
N B
NB
Bernardi
G
G
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology*; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects*; D005071:Evoked Potentials / Q000187:drug effects; D018846:Excitatory Amino Acids / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D008297:Male; D009434:Neural Pathways / Q000187:drug effects; D000078330:Oxcarbazepine; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000187:drug effects; D017661:Receptors, Presynaptic / Q000187:drug effects; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
C039775:10,11-dihydro-10-hydroxycarbamazepine; D000927:Anticonvulsants; D018846:Excitatory Amino Acids; D017470:Receptors, Glutamate; D017661:Receptors, Presynaptic; D018047:Receptors, Purinergic P1; D002220:Carbamazepine; D018698:Glutamic Acid; D000241:Adenosine; D000078330:Oxcarbazepine