Alterations of excitatory amino acids in brain may be of pathophysiological significance in thiamine-deficiency encephalopathy. The present study was undertaken to evaluate the effects of thiamine deficiency induced by the central thiamine antagonist, pyrithiamine, on the glutamate content of glutamatergic nerve terminals. Electrically-stimulated, Ca(2+)-dependent release of glutamate from hippocampal slices obtained from symptomatic pyrithiamine-treated rats was significantly decreased compared to pair-fed controls. Possible explanations for the decreased "neurotransmitter pool" of glutamate in thiamine-deficient rat brain include decreased synthesis of glutamate as a result of decreased activities of the thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase or increased release of glutamate per se. There is evidence to suggest that the latter mechanism with ensuing excitotoxic neuronal damage could be involved in the pathogenesis of selective neuronal death in thiamine deficiency. Similar mechanisms could be implicated in Wernicke's encephalopathy in humans.