Cerebral Carbohydrate Metabolism Research Articles

Caffeic acid improves memory impairment and brain glucose metabolism via ameliorating cerebral insulin and leptin signaling pathways in high-fat diet-induced hyperinsulinemic rats

This study investigated the effect of phenolic acid on memory decline and cerebral carbohydrate metabolism in rats fed a high-fat diet (HFD), which induced hyperinsulinemia. First, among eleven tested phenolic acids, caffeic acid (CA) was demonstrated to induce the highest glucose uptake capacity in insulin-resistant Neuro 2a mouse neuroblastoma cells. Next, male rats fed a HFD were treated with daily oral CA (30mg/kg body weight) for 30weeks. Cognitive performance trials were conducted to investigate the effect of CA on ameliorating memory impairment. Cerebral tissues were analyzed to determine whether CA affected brain carbohydrate metabolism and/or alleviated insulin and leptin resistance. Our results suggested that CA significantly reduced plasma glucose and insulin levels, and it alleviated insulin resistance (HOMA-IR) in HFD-induced hyperinsulinemic rats. Concurrently, passive avoidance tests revealed that orally administered CA significantly improved memory impairments in HFD rats. Western blot analysis demonstrated that CA significantly increased the expression of insulin signaling-related proteins, including the insulin receptor, phosphatidylinositol-3-kinase, Akt/protein kinase B, and insulin degrading enzyme. CA also increased the expression of leptin signaling-related proteins, including leptin receptor and pJAK2Tyr813/JAK2 in the cortex of HFD rats. These findings demonstrated that CA showed promise as a drug or food supplement for preventing the progression of dementia.

Non‐oxidative cerebral carbohydrate metabolism

Kety and Schmidt's application of the Fick Principle in the 1940s has served as the technical basis for the human cerebral metabolic studies still in use today. In this technique, arterial and jugular venous blood samples are collected, analysed for oxygen, glucose and lactate, and an arterial-jugular venous difference (AVD) is calculated. The cerebral metabolic rate is then calculated as the product of the AVD and the simultaneous measurement of cerebral blood flow. To further understand the relationship between the cerebral metabolic components, an oxygen–carbohydrate index (OCI), calculated by , or a metabolic ratio (OGI), calculated by , is used to determine how much fuel substrate is oxidized, where a value of 6 represents the complete oxidation of glucose. Glucose is considered to be the preferred cerebral oxidative fuel source under normal resting conditions, with 90% of brain glucose used oxidatively. The remaining 10% of glucose goes to non-oxidative uses, such as glycogen formation and other metabolic processes (Siesjo, 1978). On the other hand, in normal resting volunteers, the arterial jugular venous difference for lactate (AVDlac) is negative, indicating that the brain is producing and releasing lactate primarily through glycolysis. However, strenuous exercise or traumatic brain injury studies reveal that the brain has a positive AVDlac, and is therefore taking up lactate (Ide et al. 1999; Glenn et al. 2003; Soustiel & Sviri, 2007; Dalsgaard, 2006). Furthermore, the OCI/OGI can be influenced by brain activation or brain insult, with values dropping significantly due to a greater uptake of glucose and lactate relative to oxygen. In this issue of The Journal of Physiology, Larsen et al. (2009) have examined the role that the catecholamines adrenaline and noradrenaline may play in cerebral carbohydrate uptake and metabolism in normal healthy subjects. This work is a continuation of earlier studies, which found that the non-selective β-adrenergic antagonist propranolol blocked the reduction of the OCI in exercising humans (Larsen et al. 2008). In Larsen's current study, subjects were infused with either adrenaline or noradrenaline, and arterial and jugular venous blood was sampled at fixed times, allowing for the calculation of variables such as AVD, OGI and OCI. The overall findings of the current study revealed that adrenaline caused an increase in glucose uptake and a small uptake of lactate. On the other hand, noradrenaline caused an increase in glucose uptake alone, and only at the lower doses. Furthermore, adrenaline, but not noradrenaline, caused a decrease in both OCI and OGI. Therefore, their results indicate that a β2-adrenergic mechanism is responsible for the increased carbohydrate uptake. In conclusion, several important questions are raised by this research. Does adrenaline cross the blood brain barrier? As the authors suggest, are the changes in cerebral metabolism from earlier brain activation studies of Fox et al. (1988) caused by a catecholamine stress response? And ultimately, what is the fate of the excess carbohydrate uptake, i.e. where is the lactate going and through which pathways is glucose being metabolized? As the authors state, studies using stable isotopes, such as 13C-labelled glucose and lactate, are needed to further define and help answer these questions. In a recent paper by Dusick et al. (2007), [1,2-13C2]glucose was infused into traumatically brain injured patients and normal subjects. In this study, the pentose phosphate cycle activity was significantly increased in the trauma patient group as compared to normal controls, accounting in part for the increased glucose uptake seen during decreased OGI. Thus, Larsen's current study has important implications for understanding catecholamine induced cerebral responses, extending beyond exercise physiology. In disease states, such as trauma, where catecholamine levels are elevated, these findings may shed new light on the complexity of cerebral carbohydrate metabolism.

Localized sensitivity enhanced in vivo 13C MRS to detect glucose metabolism in the mouse brain

The application of in vivo 13C MR spectroscopy to mouse brain models is potentially valuable for improving the understanding of cerebral carbohydrate metabolism and glutamatergic neurotransmission in various neuropathologies. However, the low sensitivity of 13C nuclei and contaminating signals of lipids in the relatively small mouse brain make this application rather challenging. To meet these technical challenges, localized semi-adiabatic distortionless enhanced polarization transfer (DEPT) MR spectroscopy in combination with a continuous intravenous [1,6-13C2] glucose infusion was implemented to detect glucose metabolism in isoflurane-anesthetized mice at 7T. The signal enhancement and high spectral resolution obtained in these experiments enabled the separate determination of 13C label incorporation into as much as 13 metabolites from a 175 microL volume. Signal increases of glucose (C6), glutamine (C3, C4), and glutamate (C3, C4) were determined with a time resolution of 8.6 min. This study demonstrates an optimized MR method for the application of in vivo 13C MRS in mouse brain.

Some Metabolic Aspects of Septic Encephalopathy: Clinical and Experimental Study

The paper deals with the clinical and experimental studies of the pathogenetic factors underlying the development of septic encephalopathy in the presence of the systemic inflammatory response syndrome. Particular emphasis is laid on carbohydrate metabolic disturbances in the brain as one of the most important factor for neurons. The experimental section presents the age-related features of cerebral carbohydrate metabolism in the development of sepsis.

Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia.

During starvation, brain energy metabolism in humans changes toward oxidation of ketone bodies. To investigate if this shift is directly coupled to circulating blood concentrations of ketone bodies, we measured global cerebral blood flow (CBF) and global cerebral carbohydrate metabolism with the Kety-Schmidt technique before and during intravenous infusion with ketone bodies. During acute hyperketonemia (mean beta-hydroxybutyrate blood concentration 2.16 mM), cerebral uptake of ketones increased from 1.11 to 5.60 mumol.100 g-1.min-1, counterbalanced by an equivalent reduction of the cerebral glucose metabolism from 25.8 to 17.2 mumol.100 g-1.min-1, with the net result being an unchanged cerebral uptake of carbohydrates. In accordance with this, global cerebral oxygen metabolism was not significantly altered (144 vs. 135 mumol.100 g-1.min-1). The unchanged global cerebral metabolic activity was accompanied by a 39% increase in CBF from 51.0 to 70.9 ml.100 g-1.min-1. Regional analysis of the glucose metabolism by positron emission tomography-[18F]fluoro-2-deoxy-D-glucose indicated that mesencephalon does not oxidize ketone bodies to the same extent as the rest of the brain. It was concluded that the immediate oxidation of ketone bodies induced a decrease in cerebral glucose uptake in spite of an adequate glucose supply to the brain. Furthermore, acute hyperketonemia caused a resetting of the coupling between CBF and metabolism that could not be explained by alterations in arterial CO2 tension or pH.

Factors involved in the age-related alteration in the efficiency of the brain bioenergetics

The synaptic energy state may be defined by the redox state of the intramitochondrial NAD-couple (ΔG ox-red) and the phosphorylation state of adenine nucleotide system (ΔG ATP). The biological energy ‘lost’ by the system during the coupled reactions is calculated as ΔΔG = ΔG ox- red - ΔG ATP . These evaluations are performed in synaptosomes isolated from the forebrain of rats of different ages (20, 60 and 100 weeks of age) and incubated in Krebs-Henseleit-Hepes (pH 7.4) buffer, for 10 min at 24°C. The animals are submitted for 10 min to different degrees of in vivo hypoxia. To better elucidate the mechanism of action, the effects of the pretreatment with agents inducing vasodilation (papaverine), or acting on cerebral carbohydrate metabolism (hopanthenate), or on neurotransmission and cerebral metabolism (theniloxazine) are tested. In synaptosommes isolated from the forebrain of animals submitted to moderate degree of hypoxia ( Pao 2 = 32−29 mmHg) the efficiency of the system is quite similar to that observed in normoxia, with the exception of the older rats. In synaptosomes isolated from the forebrain of rats submitted to severe degree of hypoxia ( Pao 2 = 20−18 mmHg) the efficiency is altered as a function of both aging and severity of hypoxemia. Drug pretreatment may partially interfere with the ΔΔG by hypoxemia, the action being related to the rat age and hypoxic degree. The age-related decrease in the efficiency of the coupled states seems to be related to alteration in the phosphorylation state of adenine nucleotides.

The effect of electrocortical state on cerebral carbohydrate metabolism in fetal sheep

We measured hemispherical cerebral blood flow and arteriovenous differences across the cerebral cortex for glucose, oxygen, and lactate during the two primary electroencephalographic patterns (high and low voltage) in unanesthetized, near-term fetal sheep. Oxygen consumption was 127 μmol/min/100 g brain in high voltage and was 14% higher in low voltage. Glucose uptake was 19 μmol/min/100 g and was 37% higher in low voltage. Cerebral blood flow was 112 ml/min/100 g and was 29% higher in low voltage. The glucose:oxygen quotient increased from 0.91 in high voltage to 1.08 in low voltage. There was a net lactate efflux of 3.2 μmol/min/100 g during low voltage compared to a net influx of 3.3 μmol/min/100 g in high voltage. During high voltage the fetal brain uses a small amount of lactate for oxidative metabolism. During low voltage, glucose uptake exceeds the oxygen uptake needed for completely aerobic consumption, and a portion of the energy utilized by the brain is produced anaerobically.

Cerebral carbohydrate metabolism during severe ischemia in fetal sheep.

The effect of cephalic hypotension on brain metabolism was studied in 10 unanesthetized, normoxic (PaO2 greater than 17 mm Hg), late-gestation fetal lambs. Perfusion pressure (cephalic arterial minus sagittal venous pressure) was 40 +/- 1 mm Hg (SEM) during control and was reduced to 10 +/- 1 by occlusion of the Grachio-cephalic artery. Cerebral blood flow was measured with microspheres, and arterial and sagittal vein blood samples were analyzed for oxygen content, glucose, and lactate. During the occlusion, oxygen consumption decreased from 125 +/- 8 to 95 +/- 4 (p less than 0.05) (all values mumol 100 g-1 min-1), and glucose uptake increased from 20 +/- 3 to 25 +/- 1 (p less than 0.05). During the control period, there was no net lactate flux; during the occlusion, lactate excretion was 5.7 +/- 1.4 (p less than 0.005). The control glucose and oxygen uptakes demonstrated a normal 6:1 molar ratio; however, during the occlusion, 9.4 mumol 100 g-1 glucose min-1 were taken up in excess of expected aerobic glucose metabolism. If all of this glucose were anaerobically metabolized to lactate, three times the measured efflux would be produced. The transport properties of the fetal blood-brain barrier may be important factors in perinatal brain injury.

The drug treatment of senile dementia

Senile dementia, a progressive deterioration in intellectual function, is a syndrome with many causes. The commonest is Alzheimer’s disease in which cerebral carbohydrate metabolism is impaired1 and neurotransmission is defective in cholinergic,2 serotonergic3 and peptidergic systems.4 Frequently more than one cause is present, for example cerebral infarction and Alzheimer’s disease. The most important principle in the diagnosis of intellectual deterioration in the senium is to identify and remedy any partially reversible factor such as depression, pain (which may be undeclared), hypothyroidism, subdural haematoma and drug toxicity.

The effects of imidazole-4-acetic acid on cerebral carbohydrate metabolism.

The effects of intravenous administration of 50-400 mg/kg imidazole-4-acetic acid (IMA) on the carbohydrate metabolism of the rat brain were assessed by measurement of the cerebral hemisphere contents of energy phosphates and glycolytic--citric acid cycle metabolites. IMA (100-400 mg/kg) produced a spectrum of electroencephalographic (EEG) change ranging from desynchronization to electrical suppression which was associated with unchanged tissue contents of ATP, ADP, and AMP, increasing levels of phosphocreatine, glucose, and aspartate, and decreasing levels of pyruvate, lactate, alpha-ketoglutarate, and malate. The changes in glycolytic intermediates were present within 5 min of injecting IMA (200 mg/kg) and the pattern suggested a suppression of glycolysis. The EEG stage of electrical suppression with episodic spiking (400 mg/kg) was associated with a 30% reduction of cortical high-energy phosphate use. The lowest dose of IMA (50 mg/kg) resulted in episodic EEG desynchronization which was associated with no significant changes of the measured metabolites. The results indicate that IMA is associated with metabolite changes that are compatible with a state of cerebral depression and that the desynchronous EEG pattern is without a biochemical correlate of increased neuronal activity.

Cerebral carbohydrate and energy metabolism during hypoglycemia in newborn dogs.

The metabolic responses of the perinatal brain to hypoglycemia were studied in newborn dogs. Hypoglycemia, induced by the intravenous injection of regular insulin (0.2-0.3 U/g body wt), resulted in final blood glucose concentrations ranging from 0.1 to 1.5 mmol/l; blood lactate levels were little changed from normoglycemic values. Righting, sucking, and nociceptive withdrawal reflexes were progressively lost during the course of hypoglycemia. Slowing of the electroencephalogram was apparent at or below 1.5 mmol/l blood glucose and advanced to paroxysmal discharges and convulsive activity as glucose approached 0.5 mmol/l. In lightly anesthetized, paralyzed, and artificially ventilated puppies, blood glucose concentrations approximating 1.0 mmol/l were associated with a 91% reduction in cerebral glucose; the concentrations of other glycolytic intermediates (glucose 6-phosphate, fructose 6-phosphate, fructose 1,6-diphosphate, pyruvate, lactate) were unchanged from control. Further declines in blood glucose resulted in cerebral glucose levels below 0.1 mmol/kg as well as in partial depletions of all measured glycolytic intermediates including lactate. These changes reflect reduced cerebral glucose consumption and glycolytic flux. Despite the alterations in carbohydrate metabolism, both lactate/pyruvate ratios and high-energy phosphate reserves (phosphocreatine, ATP, ADP) in brain were well preserved even at the extreme of hypoglycemia. The present data, coupled with previous findings of enhanced lactic acid entry into and consumption by newborn dog brain, suggest that this metabolite serves as an important, if not the predominant, substitute fuel for cerebral oxidative metabolism during perinatal hypoglycemia.

Sequential alterations of cerebral carbohydrate metabolism associated with gamma-hydroxybutyrate

The cerebral metabolic effects of intravenous administration of 1000 mg/kg gamma-hydroxybutyrate (GHB) were studied by sequential measurement of the cerebral contents of selected glycolytic-critic cycle intermediates and energy phosphates in lightly anesthetized rats. The initial change in the glycolytic pathway occured by 2.5 min, with increases of tissues glucose-6-phosphate and decreases of fructose-1,6-diphosphate which indicated an inhibition of phosphofructokinase. This pattern was transient and was replaced at 5–15 min by increasing tissue glucose and decreasing glucose-6-phosphate which indicated an inhibition of hexokinase. The initial inhibition of phosphofructokinase was associated with functional depression, an isoelectric EEG and an increase of the tissue phosphocreatine which suggested that the observed metabolic pattern was an adaptation to the reduced energy needs of neuronal depression. Within 2.5 min of GHB injection tissue α-ketoglutarate and aspartate showed significant increases which suggested a shift in the aspartate aminotransferase reaction. Preliminary calculations indicated that the probable cause of this shift was an increase in oxaloacetate content due to GHB oxidation. The cytoplasmic NADH/NAD + ratio remained unchanged throughout the entire exposure to GHB (2.5–180 min) and thus gave no support for the hypothesis that GHB interfers with glycolysis via the restriction of free cytoplasmic NAD + required for the glyceraldehyde phosphate dehydrogenase step.

Cerebral carbohydrate metabolism during hypoglycemia and anoxia in newborn rats.

The cerebral metabolic responses to perinatal hypoglycemia and anoxia were studied in newborn rats given regular insulin (30 units per kilogram of body weight). Animals were observed for up to 2 hours with no apparent ill effects in spite of blood glucose concentrations of 0.75 mmol per liter. When exposed to 100% nitrogen at 37 degrees C, hypoglycemic animals survived only one-tenth as long as littermate controls with normal blood glucose levels (4.7 mmol/L). Pretreatment of hypoglycemic rats with glucose (10 mmol/kg) 10 and 30 minutes prior to nitrogen exposure nearly completely reversed the anoxic vulnerability. Hypoglycemia led to progressive reductions in cerebral glycogen and glucose; however, only glucose reverted to normal levels 20 minutes after systemic glucose administration. The glycolytic intermediates glucose 6-phosphate and lactate were also lower during hypoglycemia. Brain glucose levels below 0.1 mmol per kilogram were associated with a disrupted cerebral energy state, reflected by declines in phosphocreatine (33%) and adenosine triphosphate (ATP) (10%). Cerebral energy utilization (metabolic rate) was minimally reduced (-7.2%) by hypoglycemia and returned to the control value (2.36 mmol approximately P/kg/min) with glucose treatment. The cerebral energy reserves ATP, adenosine diphosphate, and phosphocreatine declined more rapidly and to a lower level in hypoglycemic rats subjected to 2 1/2 minutes of anoxia than in normoglycemic animals rendered similarly hypoxic. The findings suggest that decreased anoxic resistance of hypoglycemic newborn rats is not primarily a function of reduced brain glycogen or altered cerebral metabolic rate. The presence of endogenous cerebral glucose stores combined with continued circulating glucose (cerebrovascular perfusion) appear to be critical factors for maintaining perinatal hypoxic survival.

Energy Metabolism of Brain in Human Protein-Calorie Malnutrition

Cerebral blood flow (CBF) and carbohydrate metabolism were studied in 5 normal children and 25 children, aged 40 months or less, with varying degrees of protein-calorie malnutrition (PCM). CBF in normal children and those suffering from grade I PCM was 90.3 +/- 5.7 ml/100 g/min, a value comparable with that obtained by other investigators, but the proportion of glucose taken up by the brain which combined with oxygen, the oxygen/glucose index (OGI), was 65.8%, indicating significant conversion of glucose into lactic acid. Cerebral lactic acid production was 45.3 micronM/100 g/min, and the respiratory quotient (R.Q.) was 1.00. With increasing severity of PCM, there was increased glucose utilization and a progressive reduction in the OGI. In grade IV PCM, CBF was 68.7 +/- 5.4ml/100g/min, and the OGI was 34.7%. Cerebral lactic acid production was 27.4 micronM/100 g/min, and the R.Q. rose to 1.52. These findings suggest that in severe human PCM the proportion of glucose undergoing aerobic oxidation is reduced, and that in addition to being converted to lactic acid, a significant proportion of glucose is transformed by the brain into long chain fatty acids.

Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts.

Rats were made chronically hyperammonemic by portal-systemic shunting and, 8 wk later, were subjected to acute ammonia intoxication by the intraperitoneal injection of 5.2 mmol/kg of ammonium acetate. In free-ranging animals, ammonia treatment induced a brief period of precoma (10-15 min) that progressed into deep, anesthetic coma lasting for several hours and was associated with a high mortality. In paralyzed, artificially ventilated animals that were lightly anesthetized with nitrous oxide, acute ammonia intoxication caused major disturbances of cerebral carbohydrate, amino acid, and energy metabolism that correlated in time with the change in functional state. At 10 min after injection (precoma), the concentrations of most glycolytic intermediates were increased, as was the lactate/pyruvate ratio. Citrate declined, despite a twofold rise in pyruvate, suggesting that the conversion of pyruvate to citrate had been impaired. Concentrations of phosphocreatine, and of the putative neurotransmitters, glutamate and aspartate, declined during precoma, but the concentrations of the adenine nucleotides in the cerebral hemispheres, cerebellum, and brain stem remained within normal limits. At 60 min after injection (coma), ATP declined in all regions of brain; the reduction in total high-energy phosphates was most notable in the brain stem. The findings indicate that cerebral dysfunction in chronic, relapsing ammonia intoxication is not due to primary energy failure. Rather, it is suggested that ammonia-induced depletion of glutamic and aspartic acids, and inhibition of the malate-asparate hydrogen shuttle are the dominant neurochemical lesions.

Cerebral carbohydrate metabolism during acute carbon monoxide intoxication

The cerebral metabolic effects of 2.5, 5, 7.5, 10, 20, 30 and 60 min exposure to 1% CO were studied in lightly anesthetized rats by measurement of cerebral cortical contents of selected glycolytic and citric acid cycle intermediates, as well as tissue energy phosphates. The initial change in the glycolytic sequence occurred at 2.5 min with decreases in tissue glucose and glucose-6-phosphate and increases in fructose-1,6-diphosphate which indicated an activation of phosphofructokinase and hexokinase. The “crossover” pattern between glucose-6-phosphate and fructose-1,6-diphosphate was present at 5, 7.5 and 10 min, but not at 20, 30 and 60 min and thus confirmed previous observations that detection of phosphofructokinase activation in acute unifactorial cerebral hypoxia requires tissue study during the early phases of the experimental exposure. The initial activation of phosphofructokinase occurred in the absence of detectable changes in the tissue content of ATP, ADP, AMP or phosphocreatine and therefore suggested that an imbalance of tissue energy homeostasis is not a prerequisite for the activation of glycolysis in CO intoxication. One percent CO resulted in an increasing malate/oxaloacetate ratio at 5 min, followed by a decrease in α-ketoglutarate and aspartate at 7.5 min which suggested a shift in the aspartate aminotransferase reaction towards the replenishment of oxaloacetate removed via the malate dehydrogenase reaction. Subsequent increases in α-ketoglutarate at 10, 20, 30 and 60 min were associated with increases in alanine, indicating a contributing role for a secondary shift of the alanine aminotransferase reaction in the replenishment of α-ketoglutarate. A comparison of the CO induced changes in the glycolytic and citric acid cycle pathways with those seen in acute hypoxemia indicates no basic qualitative differences in the metabolic responses of brain tissue to the two conditions.

Pneumococcal Meningitis: A Clinical and Laboratory Study

Forty-two patients who were admitted consecutively with pneumococcal meningitis during an 18-month period were studied in Ahmadu Bello University Hospital, Zaria, Nigeria. The disease was seen most frequently in older children and young adults. A predisposing condition was found in only four patients. Counter-current immunoelectrophoresis was found to be a rapid and effective method of diagnosis: pneumococcal polysaccharide antigen was found in the initial cerebrospinal fluid (CSF) sample from all but one of the patients. Detailed physiological studies carried out in two patients showed profound disturbances of cerebral carbohydrate metabolism and an increase in cerebral vascular resistance. Twenty patients died (48 per cent) in spite of treatment with large doses of penicillin. A fatal outcome was associated with impairment of consciousness on admission, a low CSF white cell count and a high CSF antigen titre. It is suggested that marked changes in cerebral carbohydrate metabolism, and perhaps vascular damage, play important roles in producing severe brain damage in patients with pneumococcal meningitis and that defective CSF polymorphoneutrophil leukocyte function may contribute to the failure of the infection to respond satisfactorily to antibiotic therapy.

Changes in cerebral carbohydrate metabolism in the rat after acute and chronic treatment with, and withdrawal of, methamphetamine

Groups of rats were treated with methamphetamine as follows: “acute”, single intraperitoneal injection (5 mg/kg body wt); “chronic”, receiving the drug in the drinking water in concentrations which increased from 5 mg/kg/24 hr initially to 40 mg/kg/24 hr after 3 weeks; “withdrawn”, treated identically to the chronic group but given drug-free water for the final 24 hr before death. All groups, with controls, were injected with 14C glucose at various times (5–15 min) before death by rapid freezing in liquid N 2. Changes observed in the brains of the acute group (increased levels of lactale. decreased levels of glycogen and increased rates of labelling of the glycogen) disappeared on chronic treatment and were reversed in the “withdrawn” group. It is suggested that the evidence is in favour of habituation on chronic treatment of methamphetamine and that the effects of withdrawal, similar as they were to those of a depressant drug, indicate that dependence has developed.

Cerebral carbohydrate metabolism during acute hypoxia and recovery.

Abstract— The levels of ATP, ADP, AMP and phosphocreatine, of four amino acids, and of 11 intermediates of carbohydrate metabolism in mouse brain were determined after: (1) various degrees of hypoxia; (2) hypoxia combined with anaesthesia; and (3) recovery from severe hypoxia. Glycogen decreased and lactate rose markedly in hypoxia, but levels of ATP and phosphocreatine were normal or near normal even when convulsions and respiratory collapse appeared imminent.During 30 s of complete ischaemia (decapitation) the decline in cerebral ATP and phosphocreatine and the increase in AMP was less in mice previously rendered hypoxic than in control mice. From the changes we calculated that the metabolic rate had decreased by 15 per cent or more during 30 min of hypoxia.Hypoxia was also associated with decreases of cerebral 6‐phosphogluconate and aspartate, and increases in alanine, γ‐aminobutyrate, α‐ketoglutarate, malate, pyruvate, and the lactate :pyruvate ratio. Following recovery in air (10 min), increases were observed in glucose (200 per cent), glucose‐6‐phosphate, phosphocreatine and citrate, and there was a fall in fructose‐1, 6‐diphosphale.Similar measurements were made in samples from cerebral cortex, cerebellum, midbrain and medulla. Severe hypoxia produced significant increases in lactate and decreases in glycogen in all areas; γ‐aminobutyrate levels increased in cerebral cortex and brain stem, but not in cerebellum. No significant changes occurred in ATP and only in cerebral cortex was there a significant fall in phosphocreatine.Phosphocreatine, ATP and glycogen were determined by quantitative histochemical methods in four areas of medulla oblongata, including the physiological respiratory centre of the ventromedial portion. After hypoxia, ATP was unchanged throughout and the changes (decreases) in phosphocreatine and glycogen were principally confined to dorsal medulla, notably the lateral zone.Thus there is no evidence that respiratory failure is caused by a ‘power’ failure in the respiratory centre. It is suggested that in extremis a protective mechanism may cause neurons to cease firing before high‐energy phosphate stores have been exhausted.

The effects of cyclopropane on cerebral and systemic carbohydrate metabolism.

The effects of cyclopropane on cerebral and systemic carbohydrate metabolism.