SELECTIVE-INHIBITION OF THE TRICARBOXYLIC-ACID CYCLE OF GABAERGIC NEURONS WITH 3-NITROPROPIONIC ACID IN-VIVO

The effects of 3-nitropropionic acid (3-NPA), an inhibitor of succinat e dehydrogenase, on cerebral metabolism were investigated in mice by N MR spectroscopy. 3-NPA, 180 mg/kg, caused a dramatic buildup of succin ate. Succinate was labeled 5.5 times better from [1-C-13]glucose than from [2-C-13]acetate, showing a predominantly neuronal accumulation. [ 1(-13)C]Glucose labeled GABA in the C-2 position only, compatible with inhibition of the tricarboxylic acid (TCA) cycle associated with GABA formation, at the level of succinate dehydrogenase. Aspartate was not labeled by [1(-13)C]glucose in 3-NPA-intoxicated animals, In contrast , [1(-13)C]glucose labeled glutamate in the C-2, C-3, and C-4 position s showing uninhibited cycling of label in the TCA cycle associated wit h the large, neuronal pool of glutamate. The labeling of glutamine, an d hence GABA, from [2(-13)C]-acetate showed that the TCA cycle of glia l cells was unaffected by 3-NPA and that transfer of glutamine from gl ia to neurons took place during 3-NPA intoxication. The high C-13 enri chment of the C-2 position of glutamine from [1(-13)C]glucose showed t hat pyruvate carboxylation was active in glia during 3-NPA intoxicatio n. These findings suggest that 3-NPA in the initial phase of intoxicat ion fairly selectively inhibited the TCA cycle of GABAergic neurons; w hereas the TCA cycle of glia remained uninhibited as did the TCA cycle associated with the large neuronal pool of glutamate, which includes glutamatergic neurons. This may help explain why the caudoputamen, whi ch is especially rich in GABAergic neurons, selectively undergoes dege neration both in humans and animals intoxicated with 3-NPA. Further, t he present results may be of relevance for the study of basal ganglia disorders such as Huntington's disease.