Phenytoin, tetrodotoxin, and acetylcholine release

To determine if phenytoin reduces depolarization-linked acetylcholine release from synaptosomes solely by interacting with Na+, the effect of phenytoin (100 to 200 microM) and/or tetrodotoxin (1 microM) on ACh release was assayed in synaptosomes depolarized with either KCl 56 mM or veratridine 10 microM. Phenytoin reduced release in both depolarizing solutions. In KCl the effect of phenytoin was greater at 200 microM than 100 microM but with veratridine, phenytoin 200 microM was not more effective than 100 microM. Tetrodotoxin failed to affect release induced by KCl but the effect of tetrodotoxin and phenytoin on veratridine-stimulated release was much greater than that with phenytoin alone 100 microM. In conclusion, the inhibition of acetylcholine release by phenytoin must be independent of any effect of the drug on Na conductance.