Metabolic Compartmentation in the Brain: Metabolism of a Tricarboxylic Acid Cycle Intermediate, [1,4‐14c] Succinate, After Intracerebral Administration

The metabolism of a tricarboxylic acid cycle (cycle) intermediate, [1.4‐'14C]succinate, was studied in the brain at 2 20 min after intracerebral injection. The oxidation of [14C]succinate was rapid, as shown by the incorporation of 14C into cycle amino acids which accounted for about 30 per cent and 70 per cent of the tissue ‐“Cat 2 and 10 min respectively. During the whole experimental period the specific radioactivity of glutamine was about three times higher than that of glutamate. Thus exogenous [14C]succinate elicited signs of metabolic compartmentation similar to those seen after the administration of short chain fatty acids or amino acids. A computer programme, based on data obtained previously on the metabolic compartmentation of acetate and of glucose in the brain, was used to simulate the kinetics of labelling of cycle amino acids after an input of [1.4‐14C]succinate. The correspondence of the simulated data with the experimental results was good in the first 10 min after injection, although the deviations were significant at later time points. Incorporation of 14C into GABA was very low (< 1 per cent of the amino acid ‐14C) after the injection of [1.4‐14C]succinate. Further, labelled GABA formation was not detected in the decapitated rat brain labelled in vivo with [1.4‐14C]succinate 2 min beforehand. Since the oxidation of [l,4‐14C]succinate via the cycle yields unlabellcd GABA. whereas the reversal of the reactions in the GABA bypath may introduce 14C from succinate into the GABA pool, the results indicate that this reversal is negligible even under the most favourable conditions, i.e. post mortem when both the NADH/NAD+ ratios and [14C]succinate concentrations arc high. The observations are therefore consistent with the view that glutamate is the predominant and probably the only source of GABA carbon in the brain both in vivo and post mortem.