FREQUENCY-DEPENDENT INHIBITION OF NEURONAL-ACTIVITY BY TOPIRAMATE IN RAT HIPPOCAMPAL SLICES

1 Topiramate is a structurally novel anticonvulsant which was recently approved for adjunctive therapy in partial and secondarily generalize d seizures. The present study was aimed at elucidating the mechanisms underlying the anticonvulsant efficacy of topiramate using intra- and extracellular recording techniques in the in vitro hippocampal slices. 2 When stimuli were delivered every 20 s, topiramate had no measurabl e effect on both field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs). However, increasing the stimulation frequenc y from 0.05-0.2 Hz, topiramate significantly decreased the slope of fE PSP and the amplitude of PS in a concentration-dependent manner. The a mplitude of presynaptic fiber volley was also reduced. 3 Topiramate di d not affect the magnitude of paired-pulse inhibition and monosynaptic ally evoked inhibitory postsynaptic potentials (IPSPs). 4 Sustained re petitive firing was elicited by injection of long duration (500 ms) de polarizing current pulses (500 - 800 pA). Superfusion with topiramate significantly reduced the number of action potentials evoked by a give n current pulse. 5 After blockade of GABA receptors by bicuculline, bu rst firing which consisted of a train of several spikes riding on a la rge depolarizing wave termed paroxysmal depolarizing shift (PDS) was r ecorded. Application of topiramate reduced the duration of PDS and lat er spikes with less effect on the initial action potential. 6 These re sults suggest that frequency-dependent inhibition of neuronal activity due to blockade of Na+ channels may account largely for the anticonvu lsant efficacy of topiramate.