GLIAL FORMATION OF PYRUVATE AND LACTATE FROM TCA CYCLE INTERMEDIATES - IMPLICATIONS FOR THE INACTIVATION OF TRANSMITTER AMINO-ACIDS

Cerebral formation of lactate via the tricarboxylic acid (TCA) cycle w as investigated through the labeling of lactate from [2-C-13]acetate a nd [1-C-13]glucose as shown by C-13 NMR spectroscopy. In fasted mice t hat had received [2-C-13]acetate intravenously, brain lactate C-2 and C-3 were labeled at 5, 15, and 30 min, reflecting formation of pyruvat e and hence lactate from TCA cycle intermediates. In contrast, [1-C-13 ]glucose strongly labeled lactate C-3, reflecting glycolysis, whereas lactate C-2 was weakly labeled only at 15 min. These data show that fo rmation of pyruvate, and hence lactate, from TCA cycle intermediates t ook place predominantly in the acetate-metabolizing compartment, i.e., glia. The enrichment of total brain lactate from [2-C-13]acetate reac hed similar to 1% in both the C-2 and the C-3 position in fasted mice. It was calculated that this could account for 20% of the lactate form ed in the glial compartment. In fasted mice, there was no significant difference between the labeling of lactate C-2 and C-3 from [2-C-13]ac etate, whereas in fed mice, lactate C-3 was more highly labeled than t he C-2, reflecting adaptive metabolic changes in glia in response to t he nutritional state of the animal. It is hypothesized that conversion of TCA cycle intermediates into pyruvate and lactate may be operative in the glial metabolism of extracellular glutamate and GABA in vivo. Given the vasodilating effect of lactate on cerebral vessels, which ar e ensheathed by astrocytic processes, conversion of glutamate and GABA into lactate could be one mechanism mediating increases in cerebral b lood flow during nervous activity.