Primidone but not phenylethylmalonamide, a major metabolite, increases nerve-evoked transmitter release at the frog neuromuscular junction.

The fundamental responses of primidone and phenylethylmalonamide (PEMA), a major metabolite, were investigated electrophysiologically at the frog (Rana pipiens) neuromuscular junction. Concentrations of 0.2 to 1.,0 mM of each drug were used. Primidone significantly increased nerve-evoked transmitter release in a dose-dependent manner up to 186% of control at 1.0 mM concentration, whereas PEMA had no significant effect. In a separate set of experiments in which the sciatic nerve was not stimulated, primidone significantly increased transmitter release in high external K+ (7.5 mM) (no Mg++), but had no significant effect in normal K+ (2.5 mM (no Mg++). The effect of primidone in high K+ diminished in the presence of Mg++ or of decreased Ca++; PEMA also increased the frequency of MEPPs in high K+, but this effect was not sustained and diminished slowly to control values over a period of 50 min. In addition to its predominant presynaptic action, primidone also decreased MEPP amplitude to 79% of control compatible with the relatively small postjunctional depressant action, whereas PEMA had no effect. Propylene glycol, the solvent used for primidone, did not alter the effects of the drug. In conclusion, primidone but not PEMA has a predominant presynaptic action resulting in a dose-dependent increase in nerve-stimulated transmitter release and EPP amplitude.