Treatment of rats with the central
thiamine antagonist,
pyrithiamine, results in severe neurological symptoms such as loss of righting reflex. Measurement of
gamma-aminobutyric acid (
GABA) content of brain tissue from symptomatic
pyrithiamine-treated (PT) rats revealed significant reductions in thalamus, cerebellum, and pons.
GABA content of cerebral cortex, however, was unaltered. Activities of the
thiamine-dependent
enzyme alpha-ketoglutarate dehydrogenase (alpha KGDH) were reduced in parallel with the
GABA changes. On the other hand, activities of the
GABA-synthetic
enzyme glutamic acid decarboxylase (GAD) remained within normal limits, with the exception of a small but significant decrease in thalamus of symptomatic PT rats. Affinities and densities of high-affinity [3H]
muscimol binding sites on crude cerebral membrane preparations from symptomatic PT rats were unchanged.
Thiamine administration to symptomatic animals resulted in correction of abnormal righting reflexes and in normalization of decreased
GABA levels and reduced alpha KGDH activities in cerebellum and pons. Thalamic
GABA levels and alpha KGDH activities, on the other hand, remained significantly lower than normal. These results suggest that the reversible symptoms of
pyrithiamine treatment may result from imparied
GABA synthesis in cerebellum and pons of these animals. Similar mechanisms may play a role in the pathogenesis of the reversible symptoms of
Wernicke's encephalopathy in man.