An acute bout of pyrithiamine-induced thiamine deficiency (PTD) produces pathologic lesions within thalamus, mammillary body, and periventricular regions of rat brain. The biological bases for these pathologic changes and their selective distribution within the brain are unclear. The type of tissue damage observed within the thalamus of PTD rats closely resembles that observed following anoxic-ischemic insults and suggests the involvement of excitotoxic amino acids in its pathogenesis. The effects of the N-methyl-D-aspartate receptor antagonist MK-801 (3 mg/kg, i. p.) on brain lesions and amino acid changes have been assessed in rats killed during the late acute stages of PTD. A marked loss of neurons within midline intralaminar nuclei and the posterior nuclear group of the thalamus were observed in the early acute stage of PTD treatment. In the late acute stage, these changes were present throughout the entire thalamus and extended caudally to the periacqueductal gray and mesencephalic tegmentum. Hemorrhagic lesions were observed only in the late acute group and were the primary lesion within the mammillary body and medial and lateral geniculates. No pathologic changes were observed in hippocampus, amygdala, and cortex. MK-801 administered during the late stages resulted in a marked attenuation of necrotic damage to thalamus and periacqueductal gray and a reduction in the number and size of hemorrhagic lesions. Significant reductions of aspartate and glutamate and increases of glycine were observed in 5 regions of thalamus, the hippocampus, hypothalamus, and mammillary bodies of both the early and late acute PTD groups. Levels of GABA and taurine in caudal areas were significantly elevated in the early acute stage but were unchanged from controls in the late acute group. These amino acid changes were reduced in the MK-801 treated late acute group. These observations suggest that NMDA receptors are involved the pathogenesis of PTD-induced brain lesions and that nuclei of the intralaminar and posterior nuclear groups are most vulnerable to PTD effects.