Effects of ammonia on the anaplerotic pathway and amino acid metabolism in the brain: an ex vivo 13C NMR spectroscopic study of rats after administering [2-13C]] glucose with or without ammonium acetate.

The 13C-label incorporation into glutamate, glutamine, aspartate and gamma-aminobutyric acid (GABA) from [2-13C] glucose was measured by 13C nuclear magnetic resonance (NMR) spectroscopy to directly examine the effects of ammonia on the activity of pyruvate carboxylase (i.e., the anaplerotic pathway) and the amino acid metabolism in the rat brain in vivo. Rats were sacrificed by exposure to microwaves at 7.5, 15, 30, and 60 min after an i.v. injection of [2-13C] glucose with or without ammonium acetate. After the injection of ammonium acetate, the brain contents of glutamate, aspartate and GABA had decreased, however, the percentage of 13C enrichment of C3 of glutamine, glutamate and GABA, and C2 and C3 of aspartate had increased. The 13C entered the TCA cycle via pyruvate carboxylase from [2-13C] glucose, labeling the C2 or C3 positions of aspartate, the C2 or C3 positions of glutamate and glutamine, and the C3 or C4 positions of GABA first and second turns of the tricarboxylic acid (TCA) cycle. The C4/C3 labeling ratio in GABA was lower than the analogous ratio in glutamate (C2/C3) and higher than that of glutamine (C2/C3). The order of these ratios (glutamate > GABA > glutamine) was not altered by the injection of ammonium acetate. These findings directly indicate that ammonia increases the anaplerotic pathway and that the 13C-skeletons entered glial glutamine through the anaplerotic pathway flow from glia to neuron. A fraction of the glutamine is used in the direct synthesis of GABA via glutamate, whereas the remaining fraction of glutamine passed through the neuronal TCA cycle before synthesizing GABA.     

Brain amino acid reductions in one family with chromosome 6p-linked dominantly inherited olivopontocerebellar atrophy.

We measured the levels of aspartate, glutamate, gamma-aminobutyric acid (GABA), and other amino acids in autopsied brain of 6 patients from one family (Pedigree S) with dominantly inherited olivopontocerebellar atrophy. A previous demonstration of reduced aspartate concentration in plasma of affected members of this family suggested the possibility of a generalized disorder of amino acid metabolism affecting the brain. As compared with the control levels, mean levels of aspartate and glutamate were markedly reduced by about 70 and 40%, respectively, in the degenerated cerebellar cortex from the patients. Since the cerebellar aspartate reduction likely exceeds the amount that could be explained by neuronal loss, other factors such as abnormal aspartate metabolism, neurotransmitter turnover, or both are probably involved. Mean aspartate, glutamate, and GABA levels were also reduced by about 10 to 30% in most of the 16 examined extracerebellar brain areas in which no or, at most, mild neuronal cell loss was observed by semiquantitative estimation. Concentrations of taurine, glutamine, and omicron-phosphoethanolamine were normal in all brain areas examined. Our biochemical data provide support to the presence of a generalized, but quantitatively mild, disturbance in amino acid metabolism in patients with olivopontocerebellar atrophy from Pedigree S. The regionally widespread amino acid reductions in the brain, of as yet unknown pathophysiological significance, could be due to a failure of one or more enzymes involved in aspartate and glutamate metabolism.     

Effects of ammonia on the anaplerotic pathway and amino acid metabolism in the brain: an ex vivo C NMR spectroscopic study of rats after administering [2-C] glucose with or without ammonium acetate

The ¹³C-label incorporation into glutamate, glutamine, aspartate and γ-aminobutyric acid (GABA) from [2-¹³C] glucose was measured by ¹³C nuclear magnetic resonance (NMR) spectroscopy to directly examine the effects of ammonia on the activity of pyruvate carboxylase (i.e., the anaplerotic pathway) and the amino acid metabolism in the rat brain in vivo. Rats were sacrificed by exposure to microwaves at 7.5, 15, 30, and 60 min after an i.v. injection of [2-¹³C] glucose with or without ammonium acetate. After the injection of ammonium acetate, the brain contents of glutamate, aspartate and GABA had decreased, however, the percentage of ¹³C enrichment of C3 of glutamine, glutamate and GABA, and C2 and C3 of aspartate had increased. The ¹³C entered the TCA cycle via pyruvate carboxylase from [2-¹³C] glucose, labeling the C2 or C3 positions of aspartate, the C2 or C3 positions of glutamate and glutamine, and the C3 or C4 positions of GABA first and second turns of the tricarboxylic acid (TCA) cycle. The C4/C3 labeling ratio in GABA was lower than the analogous ratio in glutamate (C2/C3) and higher than that of glutamine (C2/C3). The order of these ratios (glutamate>GABA>glutamine) was not altered by the injection of ammonium acetate. These findings directly indicate that ammonia increases the anaplerotic pathway and that the ¹³C-skeletons entered glial glutamine through the anaplerotic pathway flow from glia to neuron. A fraction of the glutamine is used in the direct synthesis of GABA via glutamate, whereas the remaining fraction of glutamine passed through the neuronal TCA cycle before synthesizing GABA.     

Effects of oral cadmium exposure through puberty on plasma prolactin and gonadotropin levels and amino acid contents in various brain areas in pubertal male rats

This work was undertaken to analyze if the effects of oral cadmium exposure through puberty, on plasma prolactin and gonadotropin levels are mediated by changes in amino acid contents in various brain areas in male rats. The contents of glutamate, glutamine, aspartate, GABA and taurine in the median eminence, anterior, mediobasal and posterior hypothalamus and prefrontal cortex in pubertal male rats exposed to 50 ppm of cadmium chloride (CdCl2) in the drinking waterfor 1 month (through puberty) were measured by high performance liquid chromatography (HPLC). Plasma prolactin, LH and FSH levels were measured by specific RIA methodology. Plasma prolactin levels decreased after cadmium exposure, whereas plasma levels of LH and FSH were not changed by the metal administration. After cadmium exposure, both glutamine and glutamate contents decreased in the median eminence and in anterior and posterior hypothalamus. Metal exposure also decreased aspartate content in anterior and posterior hypothalamus, but increased it in prefrontal cortex. GABA content decreased in any studied brain region after cadmium administration. Besides, the metal decreased taurine content in the median eminence, anterior and posterior hypothalamus and in prefrontal cortex. The results suggest that cadmium effects on plasma prolactin levels may be partially explained by the changes in aspartate, glutamate or taurine contents, but not by the decrease in GABA content in the brain regions studied.     

Effects of neonatal hypothyroidism on brain development: analysis of brain metabolites using high resolution phosphorus and proton magnetic resonance (NMR) spectroscopy

The brain metabolites were studied in the neonatal hypothyroid rat brain using 31P and 1H nuclear magnetic resonance (NMR) spectroscopy. In vivo 31P spectroscopy of the brains in hypothyroid rats showed the tendency of decrease in phosphocreatine/Pi and phosphocreatine/ATP ratio, suggesting suppressed brain energy status. On proton analysis using perchloric acid extracts of the brain, 10 metabolites were easily recognized. Quantitative analysis of individual metabolites revealed decreased contents of GABA, NAA (N-acetyl aspartate) and phosphocreatine and increased contents of taurine in hypothyroid rat. It was concluded that NMR is a useful and promising tool to evaluate brain metabolites.     

1-13C]Glucose entry in neuronal and astrocytic intermediary metabolism of aged rats. A study of the effects of nicergoline treatment by 13C NMR spectroscopy

Age-related changes in glucose utilization through the TCA cycle were studied using [1-13C]glucose and 13C, 1H NMR spectroscopy on rat brain extracts. Significant increases in lactate levels, as well as in creatine/phosphocreatine ratios (Cr/PCr), and a decrease in N-acetyl-aspartate (NAA) and aspartate levels were observed in aged rat brains as compared to adult animals following glucose administration. The total amount of 13C from [1-13C]glucose incorporated in glutamate, glutamine, aspartate and GABA was significantly decreased in control aged rat brains as compared to adult brains. The results showed a decrease in oxidative glucose utilization of control aged rat brains. The long-term nicergoline treatment increased NAA and glutamate levels, and decreased the lactate levels as well as the Cr/PCr ratios in aged rat brains as compared to adult rats. The total amount of 13C incorporated in glutamate, glutamine, aspartate, NAA and GABA was increased by nicergoline treatment, showing an improvement in oxidative glucose metabolism in aged brains. A significant increase in pyruvate carboxylase/pyruvate dehydrogenase activity (PC/PDH) in the synthesis of glutamate in nicergoline-treated aged rats is consistent with an increase in the transport of glutamine from glia to neurons for conversion into glutamate. In adult rat brains, no effect of nicergoline on glutamate PC/PDH activity was observed, although an increase in PC/PDH activity in glutamine was, suggesting that nicergoline affects the glutamate/glutamine cycle between neurons and glia in different ways depending on the age of animals. These results provide new insights into the effects of nicergoline on the CNS.     

Brain glutamine synthesis requires neuronal-born aspartate as amino donor for glial glutamate formation

The glutamate–glutamine cycle faces a drain of glutamate by oxidation, which is balanced by the anaplerotic synthesis of glutamate and glutamine in astrocytes. De novo synthesis of glutamate by astrocytes requires an amino group whose origin is unknown. The deficiency in Aralar/AGC1, the main mitochondrial carrier for aspartate–glutamate expressed in brain, results in a drastic fall in brain glutamine production but a modest decrease in brain glutamate levels, which is not due to decreases in neuronal or synaptosomal glutamate content. In vivo ¹³C nuclear magnetic resonance labeling with ¹³C₂acetate or (1-¹³C) glucose showed that the drop in brain glutamine is due to a failure in glial glutamate synthesis. Aralar deficiency induces a decrease in aspartate content, an increase in lactate production, and lactate-to-pyruvate ratio in cultured neurons but not in cultured astrocytes, indicating that Aralar is only functional in neurons. We find that aspartate, but not other amino acids, increases glutamate synthesis in both control and aralar-deficient astrocytes, mainly by serving as amino donor. These findings suggest the existence of a neuron-to-astrocyte aspartate transcellular pathway required for astrocyte glutamate synthesis and subsequent glutamine formation. This pathway may provide a mechanism to transfer neuronal-born redox equivalents to mitochondria in astrocytes.     

Effects of pharmacological manipulation on neurotransmitter and other amino acid levels in the CSF of the Senegalese baboonPapio papio

The concentrations of GABA, glutamate, aspartate, glycine, taurine, glutamine, asparagine and alanine were determined in the CSF of 10 Senegalese baboons (Papio papio) following initial ketamine anaesthesia and subsequent administration (4 h later) of different compounds known to alter either inhibitory or excitatory neurotransmission. Ketamine itself was apparently without effect as the administration of a second dose of ketamine did not significantly alter the levels of any of the amino acids studied, although GABA levels tended to decrease. The presence of haemolysed material in occasional samples was associated with high GABA, glutamate, aspartate, taurine and asparagine levels. Therefore only haemolysate-free samples were included for analysis. Of the compounds administered, gamma-vinyl GABA had the most evident effect on CSF amino acid levels, increasing GABA (greater than 5-fold) and decreasing glutamate (greater than 50%), aspartate (40-50%), asparagine (20%) and alanine (30-35%) levels. The changes in GABA, glutamate and aspartate were still apparent 24 h post-gamma-vinyl GABA administration. In contrast, sodium valproate did not significantly alter the CSF levels of any of the amino acids studied. Upon acute administration allylglycine decreased the CSF concentrations of GABA and alanine, but not glutamate. These alterations are unlikely related to the occurrence of allylglycine-induced convulsions (in 2 of 4 experiments) as electroconvulsive shock did not alter CSF amino acid levels. During the experimental period encompassing the allylglycine injection (8 weeks), basal (initial post-ketamine, pre-drug sample) amino acid levels were abnormal with large increases in glutamate, GABA, aspartate and taurine whereas asparagine levels were below the limit of detection. Diazepam administration was followed by a significant increase in taurine and a decrease in aspartate levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurotransmitter amino acids in cerebrospinal fluid of patients with Alzheimer's disease

Summary. We measured the CSF and plasma levels of glutamate, glutamine, aspartate (only in plasma), asparagine, glutamine, glycine and GABA in 37 patients with Alzheimer's disease and in 32 matched controls. We used an ion-exchange chromatography method. When compared to controls, AD patients had higher CSF glutamate and glycine levels, higher plasma levels of aspartate and glycine, and lower plasma levels of asparagine and GABA. When expressed relative to CSF proteins, CSF levels of glutamate and glycine remained higher, and CSF asparagine levels were lower in AD patients than in controls. The CSF levels of the amino acids measured were not correlated with the clinical features of AD with the exception of plasma GABA levels with duration of the disease. Our results might suggest a possible pathogenetic role of neurotransmitter amino acids in AD. Accepted December 2, 1997; received August 30, 1997     

Amino acids in rat neostriatum: Alteration by kainic acid lesion

Unilateral stereotaxic injection of 10 nmol of the glutamomimetic substance, kainic acid, into the rat striatum caused permanent, significant decreases in the levels of glutamate (40--50%), aspartate (35--40%), taurine (20--30%) and GABA (60--70%). There were initial, transient decreases in serine, glycine and alanine which returned to normal values within 16--32 days after injection. Glutamine levels were not altered in lesioned striatum. This coincided with a 55% increase in glutamine synthetase activity in the lesioned striatum compared either to the non-injected striatum or controls injected with saline. The high affinity uptake of choline by synaptosomal preparations of lesioned striatum was decreased by 70% compared to controls whereas that of glutamate/aspartate was either unchanged or somewhat on a per mg protein basis. This latter point may be illusory in that, because of widespread neuronal destruction, the total 'synaptosomal' protein obtained from the lesioned striata was only about 50% that from control tissue. The biochemical data are consistent with the histological and behavioral effects of kainic acid administration. The unchaning glutamine levels and increase in glutamine synthetase activity are consistent with the widespread gliosis and the lack of change in glutamate/aspartate high affinity uptake is consistent with a sparing of afferent terminals. The large decrease in glutamate and aspartate is consistent with hypotheses concerning the intraneuronal localization of a major pool of these amino acids, especially in GABAergic neurons. The decrease in taurine suggests that a portion of this amino acid in striatum is probably associated with neurons destroyed by kainic acid. The bulk of the taurine, however, is therefore associated either with glial cells or the afferents to the striatum.     

Alcohol preference, behavioural reactivity and cognitive functioning in female rats exposed to a three-bottle choice paradigm

Metabolic consequences of morphine dependence and withdrawal intervention have not been well explored. In the present study, the metabolic changes in brain hippocampus, nucleus accumbens (NAc), prefrontal cortex (PFC) and striatum of rats with morphine dependence and withdrawal intervention were explored by using 1H nuclear magnetic resonance coupled with principal component analysis, partial least squares and orthogonal signal correction analysis. We found that the concentrations of neurotransmitters including glutamate, glutamine and gamma-aminobutyric acid changed differentially in hippocampus, NAc, PFC and striatum after repeated morphine treatment. Significant changes were also found in a number of cerebral metabolites including N-acetyl aspartate (NAA), lactic acid, creatine, myo-inositol and taurine. These findings indicate the profound disturbances of energy metabolism, amino acid metabolism and neurotransmitters caused by chronic morphine treatment. Interestingly, morphine-induced changes in lactic acid, creatine and NAA were clearly reversed by intervention of methadone or clonidine. Our study provides a comprehensive understanding of the metabolic alteration associated with morphine addiction and withdrawal therapy, which may help to develop new pharmacotherapies.     

Neuronal and astrocytic metabolism in a transgenic rat model of Alzheimer's disease

Regional hypometabolism of glucose in the brain is a hallmark of Alzheimer''s disease (AD). However, little is known about the specific alterations of neuronal and astrocytic metabolism involved in homeostasis of glutamate and GABA in AD. Here, we investigated the effects of amyloid β (Aβ) pathology on neuronal and astrocytic metabolism and glial-neuronal interactions in amino acid neurotransmitter homeostasis in the transgenic McGill-R-Thy1-APP rat model of AD compared with healthy controls at age 15 months. Rats were injected with [1-¹³C]glucose and [1,2-¹³C]acetate, and extracts of the hippocampal formation as well as several cortical regions were analyzed using ¹H- and ¹³C nuclear magnetic resonance spectroscopy and high-performance liquid chromatography. Reduced tricarboxylic acid cycle turnover was evident for glutamatergic and GABAergic neurons in hippocampal formation and frontal cortex, and for astrocytes in frontal cortex. Pyruvate carboxylation, which is necessary for de novo synthesis of amino acids, was decreased and affected the level of glutamine in hippocampal formation and those of glutamate, glutamine, GABA, and aspartate in the retrosplenial/cingulate cortex. Metabolic alterations were also detected in the entorhinal cortex. Overall, perturbations in energy- and neurotransmitter homeostasis, mitochondrial astrocytic and neuronal metabolism, and aspects of the glutamate–glutamine cycle were found in McGill-R-Thy1-APP rats.     

Compartmental distribution of endogenous amino acids in the substantia nigra of the rat

Using a push-pull cannula we have monitored the spontaneous efflux of 8 endogenous amino acids into perfusates of the substantia nigra of the rat. The extracellular concentrations of the amino acids were estimated and compared to their respective tissue levels. High intra-/extracellular concentration ratios were found for γ-aminobutyric acid (GABA), aspartate, glutamate and taurine. Much lower values were found for glycine, alanine, serine and glutamine. These results provide evidence for possible neurotransmitter roles for aspartate, glutamate and taurine in the substantia nigra in addition to that, long recognized, for GABA.     

犬脑干持续缺血模型氨基酸含量的动态变化

目的 :探讨氨基酸递质及调质在缺血性脑干损伤中的作用。方法 :建立犬脑干缺血模型 ,测定脑干缺血 3 0min组 ,缺血 3h、6h、12h后氨基酸的含量。结果 :与假手术组相比 ,Glu ,Asp ,Gly ,GABA ,Tau ,Ser ,Gln ,Ala及Thr的含量均随缺血时间的延长而不断增加。海风藤预处理可使缺血时Glu ,Asp及Ser含量的增高程度显著降低 ,使Gly ,GABA及Tau的增高显著加强。结论 :脑干持续缺血后Glu ,Asp及Ser可能是脑干缺血损害的生化基础。海风藤在脑干缺血中起神经保护作用     

Regional changes in transmitter amino acids during focal and generalized seizures in rats

Summary Measurement of glucose utilization after 20 minutes of seizure activity induced by the systemic administration of convulsants in paralyzed, ventilated rats demonstrates that the initial metabolic activation during kainic acid seizures is confined to the hippocampus. L-allylglycine-induced generalized seizures result in a global metabolic activation, whereas bicuculline seizures in fasted rats have little effect on brain glucose utilization after 20 minutes of seizure activity.Other metabolic changes associated with kainic acid seizures also predominate in the hippocampus, were decreases in the levels of aspartate, glutamate, taurine and glutamine, and an increase in the level of GABA are observed after 20 minutes of seizure activity. L-allylglycine seizures are associated with generalized decreases in regional GABA levels, and increases in regional glutamine levels. Bicuculline-induced changes include increases in hippocampal GABA and taurine levels, and increases in cerebellar glutamine and taurine levels. These changes can be tentatively explained in terms of known biochemical and neurophysiological mechanisms of these convulsants.     

High-field MRS study of GABA, glutamate and glutamine in social anxiety disorder: response to treatment with levetiracetam

OBJECTIVE: Abnormalities in brain gamma-aminobutyric acid (GABA) and glutamate may be relevant to the underlying pathophysiology of anxiety disorders including social anxiety disorder (SAD). METHODS: We used proton magnetic resonance spectroscopy (pMRS) to examine whole brain and regional GABA, glutamate and glutamine in patients (N=10) with SAD at baseline compared to a matched group of healthy controls (HC), and changes following 8 weeks of pharmacotherapy with levetiracetam. RESULTS: For SAD subjects, there were significantly higher whole brain levels of glutamate and glutamine, though no significant differences in GABA. In the thalamus, glutamine was higher and GABA lower for SAD subjects. There was a significant reduction in thalamic glutamine with levetiracetam treatment. CONCLUSION: Our findings provide preliminary support for impaired GABAergic and overactive glutamatergic function in social anxiety disorder and the potential relevance of changes in these systems for the anxiolytic response to levetiracetam.     

Anti-inflammatory treatment in AD mice protects against neuronal pathology

Prior studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may lower the incidence of Alzheimer's disease (AD) and delay onset or slow progression of symptoms in mouse models of AD. We examined the effects of chronic NSAID treatment in order to determine which elements of the pathological features might be ameliorated. We compared the effects of the NSAIDs ibuprofen and celecoxib on immunohistological and neurochemical markers at two different ages in APPxPS1 mice using measurements of amyloid plaque deposition, Aβ peptide levels, and neurochemical profiles using magnetic resonance spectroscopy (MRS). At 6 months of age, few neurochemical changes were observed between PSAPP mice and WT mice using MRS. Ibuprofen, but not celecoxib, treatment significantly decreased the Aβ_42/40 ratio in frontal cortex at 6 months, but overall amyloid plaque burden was unchanged. Consistent with prior findings in mouse models, at 17 months of age, there was a decrease in the neuronal markers NAA and glutamate and an increase in the astrocytic markers glutamine and myo-inositol in AD mice compared to WT. Ibuprofen provided significant protection against NAA and glutamate loss. Neither of the drugs significantly affected myo-inositol or glutamine levels. Both ibuprofen and celecoxib lowered plaque burden without a significant effect on Aβ_1–42 levels. NAA levels significantly correlated with plaque burden. These results suggest that selective NSAIDs (ibuprofen and possibly celecoxib) treatment can protect against the neuronal pathology.     

Effects of acute intoxication with hydrogen sulfide on central amino acid transmitter systems

The acute effects of hydrogen sulfide (H2S) on brain amino acid levels were examined in five regions of the rat brain following administration of either saline (controls), or 10 or 30 mg/kg i.p. of sodium hydrosulfide (NaHS). These doses represented sublethal (0.66 x LD50) as well as lethal (2 x LD50) amounts. No significant changes in amino acid levels were found in the cerebral cortex, striatum or hippocampus. In the cerebellum, aspartate and glycine levels declined at 10 mg/kg NaHS. The region showing the greatest change was the brainstem where aspartate, glutamate, glutamine, GABA, glycine and taurine and alanine all increased. It would appear then, that acute intoxication results in substantial changes in brainstem amino acid levels. As some of these amino acids have been implicated in the neuronal control of breathing, one of the underlying causes of death following H2S may be the alteration of amino acid neurotransmitter levels and metabolism resulting in the arrest of central respiratory drive.     

High-resolution magic angle spinning and 1H magnetic resonance spectroscopy reveal significantly altered neuronal metabolite profiles in CLN1 but not in CLN3

The neuronal ceroid lipofuscinoses (NCLs) are among the most severe inherited progressive neurodegenerative disorders of children. The purpose of this study was to compare the in vivo 1.5-T 1H magnetic resonance (MR) and ex vivo 14.3-T high-resolution (HR) magic angle spinning (MAS) 1H MR brain spectra of patients with infantile (CLN1) and juvenile (CLN3) types of NCL, to obtain detailed information about the alterations in the neuronal metabolite profiles in these diseases and to test the suitability of the ex vivo HR MAS (1)H MRS technique in analysis of autopsy brain tissue. Ex vivo spectra from CLN1 autopsy brain tissue (n = 9) significantly differed from those of the control (n = 9) and CLN3 (n = 5) groups, although no differences were found between the CLN3 and the control groups. Principal component analysis of ex vivo data showed that decreased levels of N-acetylaspartate (NAA), gamma-aminobutyric acid (GABA), glutamine, and glutamate as well as increased levels of inositols characterized the CLN1 spectra. Also, the intensity ratio of lipid methylene/methyl protons was decreased in spectra of CLN1 brain tissue compared with CLN3 and control brain tissue. In concordance with the ex vivo data, the in vivo spectra of late-stage patients with CLN1 (n = 3) revealed a dramatic decrease of NAA and a proportional increase of myo-inositol and lipids compared with control subjects. Again, the spectra of patients with CLN3 (n = 13) did not differ from those of controls (n = 15). In conclusion, the ex vivo and in vivo spectroscopic findings were in good agreement within all analyzed groups and revealed significant alterations in metabolite profiles in CLN1 brain tissue but not in CLN3 compared with controls. Furthermore, HR MAS 1H MR spectra facilitated refined detection of neuronal metabolites, including GABA, and composition of lipids in the autopsy brain tissue of NCL patients.     

Chronic valproate administration produces hepatic dysfunction and may delay brain maturation in infant mice

Infant mice (2 to 4 days old) received valproate (100 or 200 mg per kilogram body weight) subcutaneously once daily for 5 days. Both dosages decreased plasma beta-hydroxybutyrate levels to about one-third of the control value, in the face of normal free fatty acid and glycerol levels. At 200 mg per kilogram of valproate, there were significant decreases in brain weight and brain K content. Both doses produced metabolite changes in brain compatible with a reduced metabolic flux through the glycolytic pathway and the citric acid cycle. Valproate reduced brain aspartate but did not increase brain GABA levels in infant mice. At 200 mg per kilogram of valproate, brain glutamate decreased and taurine levels increased. Two hundred milligrams per kilogram of valproate caused a profound reduction of liver glycogen stores. The apparent decrease in cerebral metabolic rate, reduced glutamate and aspartate, and increased levels of taurine in brain may relate to the anticonvulsant action of valproate. Together with the decreased brain weight and K content, the findings are also compatible with maturational delay. Decreased ketonemia and liver glycogen content may relate to the hepatic toxicity associated with valproate administration in infants and children.