Carbamazepine inhibits L-type Ca2+ channels in cultured rat hippocampal neurons stimulated with glutamate receptor agonists

In order to better understand the mechanism(s) of action of carbamazepine ( CBZ), we studied its effects on the increase in [Ca2+](i) and [Na+](i) stim ulated by glutamate ionotropic receptor agonists, in cultured rat hippocamp al neurons, as followed by indo-1 or SBFI fluorescence, respectively. CBZ i nhibited the increase in [Ca2+](i) stimulated either by glutamate, kainate, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA), or N-methyl- D-aspartate (NMDA), in a concentration-dependent manner. In order to discri minate the effects of CBZ on the activation of glutamate receptors from pos sible effects on Ca2+ channels, we determined the inhibitory effects of Ca2 + channel blockers on [Ca2+](i) changes in the absence or in the presence o f CBZ. The presence of 1 mu M nitrendipine, 0.5 mu M omega-conotoxin GVIA ( omega-CgTx GVIA), or of both blockers, inhibited the kainate-stimulated inc rease in [Ca2+](i) by 51.6, 32.9 or 68.7%, respectively. In the presence of both 100 mu M CBZ and nitrendipine, the inhibition was similar (54.1%) to that obtained with nitrendipine alone, but in the presence of both CBZ and omega-CgTx GVIA, the inhibition was greater (54%) than that caused by omega -CgTx GVIA alone. However, CBZ did not inhibit the increase in [Na+](i) sti mulated by the glutamate receptor agonists, but inhibited the increase in [ Na+](i) due to veratridine. Tetrodotoxin, or MK-801, did not inhibit the in flux of Na+ stimulated by kainate, indicating that Na+ influx occurs mainly through the glutamate ionotropic non-NMDA receptors. Moreover, LY 303070, a specific AMPA receptor antagonist, inhibited the [Na+](i) response to kai nate or AMPA by about 70 or 80%, respectively, suggesting that AMPA recepto rs are mainly involved. Taken together, the results suggest that CBZ inhibi ts L-type Ca2+ channels and Na+ channels, but does not inhibit activation o f glutamate ionotropic receptors. (C) 1999 Elsevier Science Ltd. All rights reserved.