Weak blockade of AMPA receptor-mediated depolarisations in the rat cortical wedge by phenytoin but not lamotrigine or carbamazepine.
The effects of the anticonvulsants, lamotrigine, phenytoin and carbamazepine, were investigated on NMDA and non-NMDA receptor agonist-evoked responses and against spontaneous epileptiform discharges, in the in vitro rat cortical wedge. Lamotrigine weakly attenuated responses to (RS)-alpha-amino-3-hydroxy-5-methoxy-4-isoxazole propionic acid (AMPA) and quisqualate (IC50 values >> 100 microM), but was without effect on responses to NMDA. Phenytoin weakly, but concentration-dependently, attenuated responses to AMPA and quisqualate, but much less potently attenuated responses to NMDA (IC50 values 163, 248 and >> 300 microM, respectively). Carbamazepine (3-100 microM) significantly attenuated responses to NMDA and at 100 microM attenuated responses to AMPA and quisqualate. These effects were not concentration dependent, with the IC50 values >> 100 microM. Lamotrigine and phenytoin weakly, but concentration-dependently, reduced the frequency (IC50 values 254 and > 300 microM, respectively) and amplitude (IC50 values 141 and > 300 microM, respectively) of spontaneous epileptiform discharges, whereas carbamazepine had no effect. The results show that the anticonvulsant effects of these antiepileptics are unlikely to involve antagonism of ionotropic glutamate receptors, although blockade of non-NMDA responses may play a role in the anticonvulsant profile of phenytoin. Furthermore, the data show that clinically effective anticonvulsants do not necessarily attenuate spontaneous epileptiform discharges in the rat cortical wedge.
Phillips
I
I
CNS Biology, Knoll Pharmaceuticals Research and Development, Nottingham, UK.
Martin
K F
KF
Thompson
K S
KS
Heal
D J
DJ
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D004827:Epilepsy / Q000503:physiopathology; D005071:Evoked Potentials / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D000077213:Lamotrigine; D008297:Male; D010672:Phenytoin / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D014227:Triazines / Q000494:pharmacology*
D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D002220:Carbamazepine; D010672:Phenytoin; D000077213:Lamotrigine