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Investigation of the effects of the novel anticonvulsant compound carisbamate (RWJ‐333369) on rat piriform cortical neurones in vitro
Author(s) -
Whalley BJ,
Stephens GJ,
Constanti A
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2008.00110.x
Subject(s) - picrotoxin , inhibitory postsynaptic potential , excitatory postsynaptic potential , chemistry , pharmacology , neurotransmission , electrophysiology , neuroscience , gabaa receptor , medicine , biology , receptor , biochemistry
Background and purpose: Carisbamate is being developed for adjuvant treatment of partial onset epilepsy. Carisbamate produces anticonvulsant effects in primary generalized, complex partial and absence‐type seizure models, and exhibits neuroprotective and antiepileptogenic properties in rodent epilepsy models. Phase IIb clinical trials of carisbamate demonstrated efficacy against partial onset seizures; however, its mechanisms of action remain unknown. Here, we report the effects of carisbamate on membrane properties, evoked and spontaneous synaptic transmission and induced epileptiform discharges in layer II‐III neurones in piriform cortical brain slices. Experimental approach: Effects of carisbamate were investigated in rat piriform cortical neurones by using intracellular electrophysiological recordings. Key results: Carisbamate (50–400 µmol·L −1 ) reversibly decreased amplitude, duration and rise‐time of evoked action potentials and inhibited repetitive firing, consistent with use‐dependent Na + channel block; 150–400 µmol·L −1 carisbamate reduced neuronal input resistance, without altering membrane potential. After microelectrode intracellular Cl ‐ loading, carisbamate depolarized cells, an effect reversed by picrotoxin. Carisbamate (100–400 µmol·L −1 ) also selectively depressed lateral olfactory tract‐afferent evoked excitatory synaptic transmission (opposed by picrotoxin), consistent with activation of a presynaptic Cl ‐ conductance. Lidocaine (40–320 µmol·L −1 ) mimicked carisbamate, implying similar modes of action. Carisbamate (300–600 µmol·L −1 ) had no effect on spontaneous GABA A miniature inhibitory postsynaptic currents and at lower concentrations (50–200 µmol·L −1 ) inhibited Mg 2+ ‐free or 4‐aminopyridine‐induced seizure‐like discharges. Conclusions and implications: Carisbamate blocked evoked action potentials use‐dependently, consistent with a primary action on Na + channels and increased Cl ‐ conductances presynaptically and, under certain conditions, postsynaptically to selectively depress excitatory neurotransmission in piriform cortical layer Ia‐afferent terminals.