Phenytoin does not block hippocampal long-term potentiation or frequency potentiation.
Recently, a theoretical scheme offered mechanisms by which phenytoin exerts its antiepileptic effects. Two predictions arising from this proposal are that phenytoin would suppress alterations in the potency of excitatory neurotransmission engendered by repetitive neural activation and that this effect would be augmented by displacing the extracellular concentration of K+ ([K+]0) away from its normal resting level. In the present study, we tested these predictions by examining the effects of phenytoin on short- and long-term functional plasticity in vitro in the hippocampus. Extracellular field potentials were recorded in the CA1 region of the rat hippocampal slice in response to stimulation of the Schaeffer collaterals. Phenytoin (20 micrograms/ml) did not affect baseline excitatory neurotransmission as measured by input-output curves (population spike amplitude versus stimulus intensity) obtained at low stimulus rates. The drug also had no effect on either frequency potentiation (2.5 Hz) or long-term potentiation (50 Hz, 500 msec; or 400 Hz, 20 msec). When [K+]0 was raised to levels seen during seizures, the drug still did not alter frequency potentiation or long-term potentiation induced by either type of stimulus train. Phenytoin also had no effect on either stimulus-locked or spontaneous epileptiform bursts that appear in conjunction with elevated [K+]0 or on stimulus-locked bursts that appear in the presence of 0.75 mM extracellular calcium. These results, showing that certain forms of functional synaptic plasticity are not affected by phenytoin, suggest a means by which phenytoin could exert its antiepileptic action without interfering with normal brain function.
Stringer
J L
JL
Department of Neurology, University of Virginia Medical Center, Charlottesville 22908.
Lothman
E W
EW
D000818:Animals; D002118:Calcium / Q000378:metabolism; D046508:Culture Techniques; D004569:Electroencephalography; D005071:Evoked Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D010672:Phenytoin / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013569:Synapses / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D007473:Ion Channels; D010672:Phenytoin; D011188:Potassium; D002118:Calcium