An in vitro electrophysiological study on the effects of phenytoin, lamotrigine and gabapentin on striatal neurons

1 We performed intracellular recordings from a rat corticostriatal slice pr eparation in order to compare the electrophysiological effects of the class ical antiepileptic drug (AED) phenytoin (PHT) and the new AEDs lamotrigine (LTG) and gabapentin (GBP) on striatal neurons. 2 PHT, LTG and GBP affected neither the resting membrane potential nor the input resistance/membrane conductance of the recorded cells. In contrast, t hese agents depressed in a dose-dependent and reversible manner the current -evoked repetitive firing discharge. 3 These AEDs also reduced the amplitude of glutamatergic excitatory postsyn aptic potentials (EPSPs) evoked by cortical stimulation. However, substanti al pharmacological differences between these drugs were found. PHT was the most effective and potent agent in reducing sustained repetitive firing of action potentials, whereas LTG and GBP preferentially inhibited corticostri atal excitatory transmission. Concentrations of LTG and GBP effective in re ducing EPSPs, in fact, produced only a slight inhibition of the firing acti vity of these cells. 4 LTG, but not PHT and GBP, depressed cortically-evoked EPSPs increasing pa ired-pulse facilitation (PPF) of synaptic transmission, suggesting that a p resynaptic site of action was implicated in the effect of this drug. Accord ingly, PHT and GBP, but not LTG reduced the membrane depolarizations induce d by exogenously-applied glutamate, suggesting that these drugs preferentia lly reduce postsynaptic sensitivity to glutamate released from corticostria tal terminals. 5 These data indicate that in the striatum PHT, LTG and GBP decrease neuron al excitability by modulating multiple sites of action. The preferential mo dulation of excitatory synaptic transmission may represent the cellular sub strate for the therapeutic effects of new AEDs whose use may be potentially extended to the therapy of neurodegenerative diseases involving the basal ganglia.