This review summarizes microdialysis studies that address the question of which compounds serve as energy sources in the brain. Microdialysis was used to introduce 14C‐labeled glucose, lactate, pyruvate, glutamate, glutamine, and acetate into the interstitial fluid of the brain to observe their metabolism to 14CO2. Although glucose uptake from the systemic system supplies the carbon source for these compounds, compounds synthesized from glucose by the brain are subject to recycling including complete metabolism to CO2. Therefore, the brain utilizes multiple compounds in its domain to provide the energy needed to fulfill its function. The physiological conditions controlling metabolism and the contribution of compartmentation into different brain regions, cell types, and subcellular spaces are still unresolved. The aconitase inhibitor fluorocitrate, with a lower inhibition threshold in glial cells, was used to identify the proportion of lactate and glucose that was oxidized in glial cells versus neurons. The fluorocitrate data suggest that glial and neuronal cells are capable of utilizing both lactate and glucose for energy metabolism.

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Metabolic compartmentation of amino acid metabolism in brain is exemplified by the differential synthesis of glutamate and glutamine from the identical precursor and by the localization of the enzyme glutamine synthetase in glial cells. In the current study, we determined if the oxidative metabolism of glutamate and glutamine was also compartmentalized. The relative oxidation rates of glutamate and glutamine in the hippocampus of free-moving rats was determined by using microdialysis both to infuse the radioactive substrate and to collect 14C0 2 generated during their oxidation. At the end of the oxidation experiment, the radioactive substrate was replaced by artificial CSF, 2 mm-fractions were collected, and the specific activities of glutamate and glutamine were determined. Extrapolation of the specific activity back to the time that artificial CSF replaced 14C-amino acids in the microdialysis probe yielded an approximation of the interstitial specific activity during the oxidation. The extrapolated interstitial specific activities for [14C]glutamate and [14C]glutamine were 59 ± 18 and 2.1 ±0.5 dpm/pmol, respectively. The initial infused specific activities for [U-140] glutamate and [U-14C] glutamine were 408 ±8 and 387 ±1 dpm/pmol, respectively. The dilution of glutamine was greater than that of glutamate, consistent with the difference in concentrations of these amino acids in the interstitial space. Based on the extrapolated interstitial specific activities, the rate of glutamine oxidation exceeds that of glutamate oxidation by a factor of 5.3. These data indicate compartmentation of either uptake and/or oxidative metabolism of these two amino acids. The presence of [14C}glutamine in the interstitial space when [14C]glutamate was perfused into the brain provided further evidence for the glutamate/glutamine cycle in brain. Key Words: Brain energy metabolism-Oxidation -Microdialysis-Glutamate-Glutamine.

Two strains of Mus musculus musculus, C57BL/6J and CD-1, and Mus musculus poschiavinus, the tobacco mouse, were used to study the effects of increased gene dosage of mouse chromosome 16 (MMU 16). A developmental delay has been found in the brains of murine trisomy 16 (Ts16) fetuses. Both the brain weight (in all three strains) and DNA content (in CD-1) were reduced, while protein content was unchanged in Ts16 compared to normal littermates. The daily increments of weight and protein (except in M. m. poschiavinus) were significantly greater in Ts16. The activities of choline acetyltransferase and acetylcholinesterase and muscarinic receptor binding were reduced. Their daily increments were also reduced to less than 56% that of littermates in Ts16 brains. The rate limiting enzymes of catecholaminergic neurons, tyrosine hydroxylase and dopamine beta-hydroxylase, and the concentration of catecholamines in the brains of Ts16 animals were lower. The activities of three other catecholaminergic enzymes, DOPA decarboxylase, catechol O-methyltransferase, and monoamine oxidase, were generally elevated in Ts16 brain, as were their daily increments. These observations indicate a significant developmental alteration in the maturation of the trisomic brain and suggest future avenues for defining the effect of increased gene dosage of MMU 16 in the CNS.

The oxidative capacity of the brain for alternate substrates, glucose, lactate, pyruvate, acetate, glutamate, and glutamine was determined by using microdialysis to infuse (14)C-labeled compounds into the interstitial fluid of adult rat brain and by collecting the brain-generated (14)CO(2) from the dialysis eluate. All compounds were readily oxidized. The recovery of (14)CO(2) was enhanced for those compounds metabolically close to entry into the TCA cycle or known to have a low interstitial concentration. Two compounds, pyruvate and lactate, demonstrated reciprocal competition when added as nonradioactive competitors. Oxidation of two amino acids, (14)C-glutamate and (14)C-glutamine, was stimulated by the addition of nonradioactive acetate and pyruvate. alpha-Cyano-4-hydroxycinnamate decreased (14)C-lactate and (14)C-pyruvate oxidation, consistent with the transport of both compounds via a monocarboxylate transporter. The results of this in vivo study support the results of previous in vitro studies that showed that a wide range of compounds formed from glucose in the brain are also oxidized in the brain for energy production.