Frequency-dependent effects of phenytoin on frog junctional transmission: Presynaptic mechanisms

The action of the antiepileptic drug, phenytoin, on junctional transmission at various frequencies of synaptic activation was studied in frog nerve-muscle preparations. Intracellular recordings were made from muscle end-plates, and extracellular focal and subendothelial recordings were obtained from motor nerve terminals and their parent axons, respectively. When the motor nerve was stimulated at 100-200 Hz, exposure to the drug (0.1-0.3 mM) induced intermittent failures of junctional transmission which appeared faster as the rate of stimulation was increased. At these and at lower stimulation frequencies (30-50 Hz), in which failures of transmission occurred only rarely, phenytoin markedly limited the buildup of end-plate potential amplitude during the period of repetitive nerve stimulation (tetanic potentiation). Several lines of evidence suggest that both drug effects are consequent to a frequency-dependent depression of the action potential at motor axons and terminals, which could lead to an intermittent conduction block at the higher rates of stimulation. The selective action of phenytoin on high frequency synaptic transmission may contribute to the specificity shown by this drug in suppressing epileptic seizures while sparing normal neuronal activity.