Glucose Metabolism In Rat Brain Research Articles

Chronic fluoxetine enhances extinction therapy for PTSD by evaluating brain glucose metabolism in rats: an [18F]FDG PET study.

Recent studies suggest that selective serotonin reuptake inhibitors (SSRIs) and exposure therapies have been used to reduced footshock-induced posttraumatic stress disorder (PTSD) symptoms. However, the therapeutic effect of the combination of SSRIs treatment with exposure therapy remains a matter of debate. This study aimed to evaluate these therapeutic effect through the behavioural and the neuroimaging changes by positron emission tomography (PET) in model rats. Pavlovian fear conditioning paradigm to establish model rats, and serial PET imaging with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was performed during the control, fear-conditioning, and extinction-retrieval phases. The expression of c-Fos was used to identify neural activity. We report that fear conditioning increased glucose metabolism in the right amygdala and left primary visual cortex but decreased glucose metabolism in the left primary somatosensory cortex. After extinction retrieval, there was increased [18F]FDG uptake in the left striatum, left cochlear nucleus and right primary visual cortex but decreased uptake in the anterior cingulate cortex in the extinction group. Fluoxetine increased [18F]FDG uptake in the left hippocampus and right primary visual cortex but decreased uptake in the bilateral primary somatosensory cortex, left primary/secondary motor cortex and cuneiform nucleus. The combined therapy increased [18F]FDG uptake in the left hippocampus, left striatum, right insular cortex, left posterior parietal cortex, and right secondary visual cortex but reduced uptake in the cerebellar lobule. c-Fos expression in the hippocampal dentate gyrus and anterior cingulate cortex in the fluoxetine and combined groups was significantly higher than that in the extinction group, with no significant difference between the two groups. Chronic fluoxetine enhanced the effects of extinction training in a rat model of PTSD. In vivo PET imaging may provide a promising approach for evaluation chronic fluoxetine treatment of PTSD.

Abstinence following intermittent methylphenidate exposure dose-dependently modifies brain glucose metabolism in the rat brain.

Methylphenidate (MP) is a psychostimulant chronically prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). Additionally, MP users may take breaks from using the medication during "drug holidays," which may include short-term or long-term breaks from medication. The present study utilized fluorodeoxyglucose (FDG) positron emission tomography (PET) to analyze the effects of chronic oral MP use and abstinence on brain glucose metabolism (BGluM) in rats at two different doses: high dose (HD) and low dose (LD). The schedule of treatment was 3weeks on-treatment and 1week off-treatment for a period of 13weeks, followed by an abstinence period of 4 total weeks. Results showed that chronic MP treatment using this schedule did not lead to significant changes in BGluM when comparing the control to HD MP groups. However, significant activation in BGluM was observed after periods of abstinence between control and HD MP rats in the following brain regions: the trigeminal nucleus, reticular nucleus, inferior olive, lemniscus, mesencephalic reticular formation, inferior colliculus, and several areas of the cerebellum. These brain regions and functional brain circuit play a role in facial sensory function, the auditory pathway, organizing connections between the thalamus and cortex, motor learning, auditory function, control over eye movement, auditory information integration, and both motor and cognitive functions. These results, when considered with previous studies, indicate that MP schedule of use may have differing effects on BGluM. BGluM following long-term MP use was dependent on MP dose and schedule of use in rats. This study was conducted in non-ADHD model rats with the aim to establish an understanding of the effects of MP itself, especially given the growing chronic off-label and prescribed use of MP. Further studies are needed for analysis of the drug's effects on an ADHD model.

Long-term changes in metabolic brain network drive memory impairments in rats following neonatal hypoxia-ischemia.

Hypoxia and cerebral ischemia (HI) events are capable of triggering important changes in brain metabolism, including glucose metabolism abnormalities, which may be related to the severity of the insult. Using positron emission microtomography (microPET) with [18F]fluorodeoxyglucose (18F-FDG), this study proposes to assess abnormalities of brain glucose metabolism in adult rats previously submitted to the neonatal HI model. We hypothesize that cerebral metabolic outcomes will be associated with cognitive deficits and magnitude of brain injury. Seven-day-old rats were subjected to an HI model, induced by permanent occlusion of the right common carotid artery and systemic hypoxia. 18F-FDG-microPET was used to assess regional and whole brain glucose metabolism in rats at 60 postnatal days (PND 60). An interregional cross-correlation matrix was utilized to construct metabolic brain networks (MBN). Rats were also subjected to the Morris Water Maze (MWM) to evaluate spatial memory and their brains were processed for volumetric evaluation. Brain glucose metabolism changes were observed in adult rats after neonatal HI insult, limited to the right brain hemisphere. However, not all HI animals exhibited significant cerebral hypometabolism. Hippocampal glucose metabolism was used to stratify HI animals into HI hypometabolic (HI-h) and HI non-hypometabolic (HI non-h) groups. The HI-h group had drastic MBN disturbance, cognitive deficit, and brain tissue loss, concomitantly. Conversely, HI non-h rats had normal brain glucose metabolism and brain tissue preserved, but also presented MBN changes and spatial memory impairment. Furthermore, data showed that brain glucose metabolism correlated with cognitive deficits and brain volume outcomes. Our findings demonstrated that long-term changes in MBN drive memory impairments in adult rats subjected to neonatal hypoxic ischemia, using in vivo imaging microPET-FDG. The MBN analyses identified glucose metabolism abnormalities in HI non-h animals, which were not detected by conventional 18F-FDG standardized uptake value (SUVr) measurements. These animals exhibited a metabolic brain signature that may explain the cognitive deficit even with no identifiable brain damage.

Repeated social defeat induces transient glial activation and brain hypometabolism: A positron emission tomography imaging study

Psychosocial stress is a risk factor for the development of depression. Recent evidence suggests that glial activation could contribute to the development of depressive-like behaviour. This study aimed to evaluate in vivo whether repeated social defeat (RSD) induces short- and long-term inflammatory and metabolic alterations in the brain through positron emission tomography (PET). Male Wistar rats (n = 40) were exposed to RSD by dominant Long-Evans rats on five consecutive days. Behavioural and biochemical alterations were assessed at baseline, day 5/6 and day 24/25 after the RSD protocol. Glial activation (11C-PK11195 PET) and changes in brain metabolism (18F-FDG PET) were evaluated on day 6, 11 and 25 (short-term), and at 3 and 6 months (long-term). Defeated rats showed transient depressive- and anxiety-like behaviour, increased corticosterone and brain IL-1β levels, as well as glial activation and brain hypometabolism in the first month after RSD. During the third- and six-month follow-up, no between-group differences in any investigated parameter were found. Therefore, non-invasive PET imaging demonstrated that RSD induces transient glial activation and reduces brain glucose metabolism in rats. These imaging findings were associated with stress-induced behavioural changes and support the hypothesis that neuroinflammation could be a contributing factor in the development of depression.

Effects of isoflurane anesthesia and intravenous morphine self-administration on regional glucose metabolism ([18 F]FDG-PET) of male Sprague-Dawley rats.

Although certain drugs of abuse are known to disrupt brain glucose metabolism (BGluM), the effects of opiates on BGluM are not well characterized. Moreover, preclinical positron emission tomography (PET) studies anesthetize animals during the scan, which limits clinical applications. We investigated the effects of (i) isoflurane anesthesia and (ii) intravenous morphine self-administration (MSA) on BGluM in rats. Jugular vein cannulated adult male Sprague-Dawley rats self-administered either saline (SSA) or morphine (0.5mg/kg/infusion, 4h/day for 12days). All animals were scanned twice with [18 F]-fluoro-deoxy-glucose (FDG)-PET/CT at a baseline and at 2-day withdrawal from self-administration. After the IV injection of FDG, one batch of animals (n=14) was anesthetized with isoflurane and the other batch (n=16) was kept awake during the FDG uptake (45min). After FDG uptake, all animals were anesthetized in order to perform a PET/CT scan (30min). Isoflurane anesthesia, as compared to the awake condition, reduced BGluM in the olfactory, cortex, thalamus, and basal ganglia, while increasing BGluM in the midbrain, hypothalamus, hippocampus, and cerebellum. Morphine self-administered animals exhibited withdrawal signs (piloerection and increased defecation), drug seeking, and locomotor stimulation to morphine (0.5mg/kg) during the 2day withdrawal. The BGluM in the striatum was increased in the MSA group as compared to the SSA group; this effect was observed only in the isoflurane anesthesia, not the awake condition. These findings suggest that the choice of the FDG uptake condition may be important in preclinical PET studies and increased BGluM in the striatum may be associated with opiate seeking in withdrawal.

Cerebral glucose metabolism changes in rat brain upon forepaw electrical stimulation at different frequencies

PET imaging techniques and statistical parametric mapping analysis have been developed to identify neuronal functional activation from brain imaging. The purpose of this study was to examine the efficacy of the glucose metabolism in rat brain during forepaw electrical stimulation with different frequencies (3, 10, or 20 Hz) compared with a nonstimulated group (control). Fluorine-18 fluorodeoxyglucose was injected after confirmation of the range of normal physiology. For quantitative analysis, we used cerebral metabolism rate of glucose consumption (CMRglc) responses in the primary somatosensory cortex (S1FL) and motor cortex (M1). On comparing CMRglc responses in the contralateral S1FL and M1 with those of the ipsilateral areas in intragroup analysis, a significant increase (P<0.05) was observed in two electrical stimulation groups (10 and 20 Hz) but not at the 3 Hz level. In intergroup analysis, the CMRglc responses in the contralateral region of interest were compared with those of the control group to validate which electrical frequency conditions were appropriate to induce neuronal functional activation. Among the stimulation groups, significant increases in CMRglc response were only observed at 10 Hz (P<0.05). Therefore, 10 Hz is the most suitable frequency to confirm changes in CMRglc in the S1FL and M1 of the rat brain, and also fluorine-18 fluorodeoxyglucose PET could be useful to investigate recovery and plasticity in neurological diseases associated with primary sensory-motor cortex function.

Fatal mechanical asphyxia induces changes in energy utilization in the rat brain: An (18)F-FDG-PET study.

This study was designed to evaluate changes in brain glucose metabolism in rats following ligature strangulation. Thirteen male Wistar rats were used in the present study, divided into control (n=7) and asphyxia groups (n=6, ligature strangulation). Positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) was used to evaluate brain glucose metabolism. Rats were scanned for PET-CT, and image data co-registered with a T2WI MRI template using SPM8 software. Image J was employed to draw regions of interest (ROIs) from the MRI template and acquire ROI activity information from the PET images. In the asphyxia group vs. controls, (18)F-FDG uptake (FU) was decreased in the substantia nigra (25.26%, p<0.001), rhombencephalon (pons/medulla oblongata, 13.92%, p<0.01), hypothalamus (22.06%, p<0.01), ventral tegmentum (10.12%, p<0.05) and amygdala (12.74%, p<0.05); however, FU was increased in motor (18.21%, p<0.05) and visual cortices (19.2%, p<0.05). The glucose metabolism distribution map in the asphyxiated rat brains were substantially changed versus controls. PET with (18)F-FDG can demonstrate excitement and inhibition of different brain areas even in cases of ligature strangulation.

Changes in behavior and in brain glucose metabolism in rats after nine weeks on a high fat diet: a randomized controlled trial.

BackgroundA high-fat diet (HFD) is a well-known risk factor for cardio-cerebrovascular disease but the relationship between a HFD and depressive symptoms remains unknown.ObjectiveCompare changes in behavioral and measures of brain glucose metabolism in rats fed a HFD to those of rats fed a standard diet.MethodsTwenty male Sprague-Dawley rats were randomly assigned to a study group (n=10) that received a high fat diet for 9 weeks or a control group (n=10) that received a standard diet for 9 weeks. At baseline and at the end of the 9-week trial assessments included body weight, serum lipids (total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), the sucrose preference test, and the open field test. The rate of brain glucose metabolism in different brain regions (assessed using micro-positron emission tomography) at the end of the trial was also compared between the two groups of rats.ResultsNine weeks of a HFD in rats resulted in the expected increase in weight and changes in serum lipid levels, but it was also associated with a decreased preference for sucrose (which may be due to a loss of interest in pleasurable activities), increased weight-adjusted water intake, and a significant deactivation of the right thalamus and right striatum (based on decreased rates of glucose metabolism). In the HFD group the magnitude of the drop in the sucrose preference was strongly correlated to the magnitude of the deactivation of the right thalamus (r=0.78) and the right striatum (r=0.81).ConclusionsThese findings support hypotheses about the role of a HFD in the causal pathway for depressive symptoms. Further work is needed to clarify the underling mechanism, but it appears that the interaction between the content of the diet and the limbic system-striatum-thalamus circuit plays a role in both eating behavior and depressive symptoms.

Modeling of Brain Metabolism and Pyruvate Compartmentation Using 13C NMR in Vivo: Caution Required

Two variants of a widely used two-compartment model were prepared for fitting the time course of [1,6-(13)C2]glucose metabolism in rat brain. Features common to most models were included, but in one model the enrichment of the substrates entering the glia and neuronal citric acid cycles was allowed to differ. Furthermore, the models included the capacity to analyze multiplets arising from (13)C spin-spin coupling, known to improve parameter estimates in heart. Data analyzed were from a literature report providing time courses of [1,6-(13)C2]glucose metabolism. Four analyses were used, two comparing the effect of different pyruvate enrichment in glia and neurons, and two for determining the effect of multiplets present in the data. When fit independently, the enrichment in glial pyruvate was less than in neurons. In the absence of multiplets, fit quality and parameter values were typical of those in the literature, whereas the multiplet curves were not modeled well. This prompted the use of robust statistical analysis (the Kolmogorov-Smirnov test of goodness of fit) to determine whether individual curves were modeled appropriately. At least 50% of the curves in each experiment were considered poorly fit. It was concluded that the model does not include all metabolic features required to analyze the data.

A palatable hyperlipidic diet causes obesity and affects brain glucose metabolism in rats

BackgroundWe have previously shown that either the continuous intake of a palatable hyperlipidic diet (H) or the alternation of chow (C) and an H diet (CH regimen) induced obesity in rats. Here, we investigated whether the time of the start and duration of these feeding regimens are relevant and whether they affect brain glucose metabolism.MethodsMale Wistar rats received C, H, or CH diets during various periods of their life spans: days 30-60, days 30-90, or days 60-90. Experiments were performed the 60th or the 90th day of life. Rats were killed by decapitation. The glucose, insulin, leptin plasma concentration, and lipid content of the carcasses were determined. The brain was sliced and incubated with or without insulin for the analysis of glucose uptake, oxidation, and the conversion of [1-14C]-glucose to lipids.ResultsThe relative carcass lipid content increased in all of the H and CH groups, and the H30-60 and H30-90 groups had the highest levels. Groups H30-60, H30-90, CH30-60, and CH30-90 exhibited a higher serum glucose level. Serum leptin increased in all H groups and in the CH60-90 and CH30-90 groups. Serum insulin was elevated in the H30-60, H60-90, CH60-90, CH30-90 groups. Basal brain glucose consumption and hypothalamic insulin receptor density were lower only in the CH30-60 group. The rate of brain lipogenesis was increased in the H30-90 and CH30-90 groups.ConclusionThese findings indicate that both H and CH diet regimens increased body adiposity independent treatment and the age at which treatment was started, whereas these diets caused hyperglycemia and affected brain metabolism when started at an early age.

PK11195 might selectively suppress the quinolinic acid-induced enhancement of anaerobic glycolysis in glial cells

PK11195 was previously reported to attenuate the quinolinic acid (QUIN)-induced enhancement of glucose metabolism in rat brain. In the present study, the effect of PK11195 or anesthesia on [ 14C]2-deoxyglucose ([ 14C]DG) uptake was investigated in order to determine whether the QUIN-induced enhancement of glucose metabolism occurred in glial cells or neurons. We confirmed that the microinjection of QUIN caused a significant enhancement of [ 14C]DG uptake at 2 h after the infusion, while the co-injection of PK11195 and QUIN almost completely suppressed this enhancement of [ 14C]DG uptake. No effect of chloral hydrate anesthesia on the QUIN-induced enhancement of [ 14C]DG uptake was observed. In contrast to rats treated with QUIN, PK11195 did not affect the enhancement of [ 14C]DG uptake induced by fluorocitrate (FC); however, chloral hydrate anesthesia completely suppressed the FC-induced increase in [ 14C]DG uptake. These results indicated that the enhancement of glucose metabolism induced by QUIN mainly occurred in glial cells, and the neuroprotective effect of PK11195 in rats injected with QUIN might be related to the suppression of anaerobic glycolysis in glial cells.

Detection of Visual Activation in the Rat Brain Using 2-deoxy-2-[18F]fluoro-d-glucose and Statistical Parametric Mapping (SPM)

This study was designed to assess changes in brain glucose metabolism in rats after visual stimulation. We sought to determine whether visual activation in the rat brain could be detected using a small-animal positron emission tomography (PET) scanner and 2-deoxy-2-[(18)F]fluoro-D: -glucose (FDG). Eleven rats were divided into two groups: (a) five animals exposed to ambient light and (b) six animals stimulated by stroboscopic light (10 Hz) with one eye covered. Rats were injected with FDG and, after 45 min of visual stimulation, were sacrificed and scanned for 90 min in a dedicated PET tomograph. Images were reconstructed by a three-dimensional ordered subset expectation maximization algorithm (1.8 mm full width at half maximum). A region-of-interest (ROI) analysis was performed on 14 brain structures drawn on coronal sections. Statistical parametric mapping (SPM) adapted for small animals was also carried out. Additionally, the brains of three rats were sliced into 20-microm sections for autoradiography. Analysis of ROI data revealed significant differences between groups in the right superior colliculus, right thalamus, and brainstem (p < or = 0.05). SPM detected the same areas as the ROI approach. Autoradiographs confirmed the existence of hyperactivation in the left superior colliculus and auditory cortex. To our knowledge, this is the first report that uses FDG-PET and SPM analysis to show changes in rat brain glucose metabolism after a visual stimulus.

Detection of [1,6-13C2]-glucose metabolism in rat brain by in vivo 1H-[13C]-NMR spectroscopy.

Localized, water-suppressed (1)H-[(13)C]-NMR spectroscopy was used to detect (13)C-label accumulation in cerebral metabolites following the intravenous infusion of [1,6-(13)C(2)]-glucose (Glc). The (1)H-[(13)C]-NMR method, based on adiabatic RF pulses, 3D image-selected in vivo spectroscopy (ISIS) localization, and optimal shimming, yielded high-quality (1)H-[(13)C]-NMR spectra with optimal NMR sensitivity. As a result, the (13)C labeling of [4-(13)C]-glutamate (Glu) and [4-(13)C]-glutamine (Gln) could be detected from relatively small volumes (100 microL) with a high temporal resolution. The formation of [n-(13)C]-Glu, [n-(13)C]-Gln (n = 2 or 3), [2-(13)C]-aspartate (Asp), [3-(13)C]-Asp, [3-(13)C]-alanine (Ala), and [3-(13)C]-lactate (Lac) was also observed to be reproducible. The (13)C-label incorporation curves of [4-(13)C]-Glu and [4-(13)C]-Gln provided direct information on metabolic pathways. Using a two-compartment metabolic model, the tricarboxylic acid (TCA) cycle flux was determined as 0.52 +/- 0.04 micromol/min/g, while the glutamatergic neurotransmitter flux equaled 0.25 +/- 0.05 micromol/min/g, in good correspondence with previously determined values.

Evidence for a Central Cholinergic Deficit in Myasthenia Gravis

Back to table of contents Previous article Next article LetterFull AccessEvidence for a Central Cholinergic Deficit in Myasthenia GravisFotis Fotiou, M.D., Ph.D., and Konstantinos N. Fountoulakis, M.D., Ph.D., Fotis FotiouSearch for more papers by this author, M.D., Ph.D., and Konstantinos N. FountoulakisSearch for more papers by this author, M.D., Ph.D., 1st Neurological Clinic and 3rd Department of Psychiatry, General Hospital AHEPA, Aristotle University of Thessaloniki, GreecePublished Online:1 Nov 2000AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Myasthenia gravis (MG) manifests clinically with symptoms related to the dysfunction of acetylcholine (Ach) synaptic transmission in the neuromuscular junction. However, there is evidence that in MG patients, cholinergic transmission in the central nervous system (CNS) is also affected. This evidence includes observations of reduced REM sleep,1 electroencephalographic changes, and detection of Ach receptor antibodies in the cerebrospinal fluid of MG patients. Also, there are some studies on the mental status of MG patients. They manifest higher trait anxiety and greater suppression of anger, and nearly 20% of them were initially diagnosed as having a psychiatric disorder.2 They may show cognitive impairment3 as well.Recently, pathological pattern-reversal visual evoked potentials (PR- VEPs) in MG patients have been reported from our research group. According to the international literature, the reason for these alterations in PR-VEPs may be a dysfunction of CNS Ach receptors or an eye movement disturbance, or even both. In a second study, because eye movements that are pathological in MG affect VEPs, we recorded eye movements (with an optical method), FLASH-electroretinogram, FLASH-VEPs, and PR-VEPs in 37 MG patients. Both the eye movements and the PR-VEPs were pathological.To further investigate this issue,4 we studied 10 control subjects, 9 patients who suffered from newly diagnosed MG, and 5 patients with ocular myopathy (OM).5 Recordings of eye movements and PR-VEPs were simultaneous. PR-VEPs were obtained 1 month before and approximately 1 month after pyridostigmine treatment in MG patients. MG is considered to be a disease of the neuromuscular junction, whereas OM is a disease of the muscles and no neurotransmitters are involved in its pathogenesis. The rationale behind this design is that by studying and comparing two groups of patients with eye movement disorder, one can isolate and control for the effect of eye movements on PR-VEPs and in this way obtain a clearer picture of the possible effect of MG in the CNS.Only the MG patients' PR-VEPs differed from those of normal control subjects both before and after pyridostigmine treatment. Those of OM patients did not. Both MG and OM patients' eye movements were significantly deficient in comparison to those of control subjects.Impaired eye movements alone do not offer sufficient explanation of the pathological VEPs observed in MG patients. The results of our research group and the international literature provide substantial evidence for a CNS Ach deficit in MG. This possibility has important therapeutic implications.Acetylcholine is related to several mental disorders, including mood and cognitive disorders. A search of the international literature yielded only a few studies dealing with the issue of mental disorders in MG patients. Generally, these patients are considered to be at higher risk for a mental disorder than patients with other neurological diseases.6 It is reported that MG patients manifest higher levels of trait anxiety. They also may inhibit the expression of anger.7 It has been theorized that these two characteristics may predispose to the development of myasthenia.A retrospective study of MG patients revealed that almost 20% of them had initially received a psychiatric diagnosis.8 Young women are at increased risk to receive a diagnosis in this way. On the contrary, men usually receive a diagnosis of another somatic disorder. However, the authors of this particular study note that false psychiatric diagnosis is accompanied by higher scores on depressive scales. Depression seems to be related to the dose of anticholinesterase treatment needed and the self-reported muscular weakness.8Apart from “pure” psychiatric symptomatology, it seems that MG patients manifest lower Mini-Mental State Examination scores and also score lower in various memory tests.9 MG patients may suffer from a disorder of higher cognitive functioning that responds to therapeutic intervention.10The role of Ach in higher cognitive function is well studied and established.11–19 However, this is not so concerning a possible role for Ach in the pathogenesis of depression. The Ach role in depression (if any) is not well studied. The inhibition of behavior produced by some agents (e.g., physostigmine) that are known to increase central Ach activity suggests that an Ach-norepinephrine imbalance is central in the pathogenesis of depression.20 However, other authors propose a relationship only to personality traits.21It has also been suggested that the simultaneous increase reported in the activity of catecholamines and in measurements that reflect the hypothalamus-pituitary-adrenal axis in depressed patients indicates, in fact, an increase of Ach activity. The increase of the central cholinergic basal activity after the administration of centrally active agents like physostigmine, arecholine, and oxotremorine usually triggers or worsens the behavioral analogs of depression. Many authors suggest that pharmacologically induced changes in Ach activity could lead to the development of a model of depression by influencing other transmitter systems (e.g., GABA, serotonin, dopamine, or norepinephrine).22On the basis of observations in Alzheimer's disease patients, several authors refer to a “cholinergic threshold” below which any experience of depressed mood is impossible.23 This thinking runs counter to the proposal that reduced Ach activity in the CNS could in itself produce depression. Of course, a psychomotor inhibition would be present, and this in combination with a cognitive deficit could produce the false impression and diagnosis of depression. However, drawing conclusions would be premature. The disorder of a single neurotransmitter in the CNS is never the sole disorder of this kind present. It is therefore necessary to assess and investigate in depth the clinical neurocognitive and psychiatric symptomatology and the functioning of the neuroendocrine system in MG patients.As far as everyday clinical practice is concerned, if there is a true acetylcholine disorder in the CNS of myasthenia gravis patients, as data tend to suggest, and this disorder is accompanied by psychiatric symptomatology and higher cognitive- function deficit, then a significant question concerning the need for treatment emerges. This treatment could well be based on agents recently developed for the treatment for Alzheimer's disease. On the other hand, the prescription of antidepressants in MG patients should be made with extreme caution because of the frequent anticholinergic side effects of these agents.References1 Papazian O: Rapid eye movement sleep alteration in myasthenia gravis. Neurology 1976; 26:310–313Crossref, Google Scholar2 Rohr W: Myasthenia gravis in the frontier of psychiatric diagnosis. Psychiatr Prax 1992; 19(5):157–163Google Scholar3 Iwasaki Y, Kinoshita M, Ikeda K, et al: Neuropsychological function before and after plasma exchange in myasthenia gravis. J Neurol Sci 1993; 114:223–226Crossref, Medline, Google Scholar4 Fotiou F, Goulas A, Fountoulakis K, et al: Changes in psychophysiology of vision in myasthenia gravis. Int J Psychophysiol 1998; 29:303–310Crossref, Medline, Google Scholar5 Fotiou F, Papakostopoulos D, Hamlatzis P: Changes in the pattern reversal visual evoked potentials in myasthenia gravis. Electromyogr Clin Neurophysiol 1994; 34:171–175Medline, Google Scholar6 DePaulo JR, Folstein MF, Gordon B: Psychiatric screening on a neurological ward. Psychol Med 1980; 10:125–132Crossref, Medline, Google Scholar7 Tennant C, Wilby J, Nicholson GA: Psychological correlates of myasthenia gravis: a brief report. 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Neuroscience 1985; 14:1025–1032Google Scholar17 Davis KL, Mohs RC, Davis BM, et al: Cholinergic treatment in Alzheimer's disease: implications for future research, in Alzheimer's Disease: A Report of Progress in Research, edited by Corkin S, Davis KL, Crowdon JH, et al. New York, Raven, 1982, pp 483–494Google Scholar18 Davis KL, Yamamura HI: Cholinergic underactivity in human memory disorders. Life Sci 1978; 23:1729–1734Google Scholar19 Ezrin-Waters C, Resch L: The nucleus basalis of Meynert. Can J Neurol 1986; 13:8–14Crossref, Medline, Google Scholar20 Janowsky D, El Yousef M, Davis J, et al: A cholinergic-adrenergic hypothesis of mania and depression. Lancet 1972; ii:632–635Google Scholar21 Fritze J, Lanczik M, Sofic E, et al: Cholinergic neurotransmission seems not to be involved in depression but possibly in personality. J Psychiatry Neurosci 1995; 20:39–48Medline, Google Scholar22 Janowsky DS, Overstreet DH: The role of acetylcholine mechanisms in mood disorders, in Psychopharmacology: The Fourth Generation of Progress, edited by Bloom FE, Kupfer DJ. New York, Raven, 1994, pp 945–956Google Scholar23 Zubenko GS, Moossy J, Kopp U: Neurochemical correlates of major depression in primary dementia. Arch Neurol 1990; 47:209–214Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byMyasthenia Gravis—An Analysis of Multimodal Evoked Potentials11 August 2021 | Brain Sciences, Vol. 11, No. 8Journal of the Neurological Sciences, Vol. 368Psychogenic Myasthenia GravisFrancesca Frame, MBBCh, Sian A. Thompson, BMBCh, M.R.C.P., Ph.D., Tina Man. Malhotra, B.S., M.D., MRCPsych, Mark J. Edwards, Ph.D., M.R.C.P., and Ivana Rosenzweig, MD, Ph.D., MRCPsych1 October 2011 | The Journal of Neuropsychiatry and Clinical Neurosciences, Vol. 23, No. 4Annals of General Psychiatry, Vol. 5, No. S1 Volume 12Issue 4 November 2000Pages 514-515 Metrics PDF download History Published online 1 November 2000 Published in print 1 November 2000

Oxidative glucose metabolism in rat brain during single forepaw stimulation: a spatially localized 1H[13C] nuclear magnetic resonance study.

In the alpha-chloralose-anesthetized rat during single forepaw stimulation, a spatially localized 1H[13C] nuclear magnetic resonance spectroscopic method was used to measure the rate of cerebral [C4]-glutamate isotopic turnover from infused [1,6-(13)C]glucose. The glutamate turnover data were analyzed using a mathematical model of cerebral glucose metabolism to evaluate the tricarboxylic acid (TCA) cycle flux (V(TCA)). During stimulation the value of V(TCA) in the sensorimotor region increased from 0.47 +/- 0.06 (at rest) to 1.44 +/- 0.41 micromol x g(-1) x min(-1) (P < 0.01) in the contralateral hemispheric compartment (24 mm3) and to 0.65 +/- 0.10 micromol x g(-1) x min(-1) (P < 0.03) in the ipsilateral side. Each V(TCA) value was converted to the cerebral metabolic rates of glucose oxidation (oxidative-CMR(glc)) and oxygen consumption (CMR(O2)). These rates were corrected for partial-volume based on activation maps obtained by blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI). The percent increase and the absolute value of oxidative-CMR(glc) in the activated regions are similar to values reported previously for total-CMR(glc) using the same activation paradigm. This indicates that the large majority of energy required for brain activation, in going from the resting to an activated state, is supplied by glucose oxidation. The level of activity during stimulation is relevant to awake animals because the oxidative-CMR(glc) (1.05 +/- 0.28 micromol x g(-1) x min(-1); current study) is in the range of total-CMR(glc) previously reported for awake rats undergoing physiologic activation (0.7-1.4 micromol x g(-1) x min(-1)). It is concluded that oxidative glycolysis is the main source of energy for increased brain activity and a positive BOLD fMRI signal-change occurs in conjunction with a large increase in CMR(O2).

Low dose raclopride spares the extrapyramidal system in rat brain from metabolic effects

The effect of a highly selective dopamine D 2 receptor antagonist, raclopride ((−)-(S)-3,5-dichloro-N-(1-ethyl-2-pyrrolidinyl) methyl-6-methoxysalicylamide tartrate), on regional cerebral glucose metabolism in rat brain was determined using [ 14C]2-deoxyglucose autoradiography, and compared to a typical neuroleptic, haloperidol. Based on preclinical biochemistry and early clinical trial reports, it was hypothesized that raclopride would fail to functionally affect brain regions putatively involved with motor function, while altering psychosis-related regions. Raclopride at a low dose (1.5 mg/kg) significantly reduced regional cerebral glucose metabolism in neocortical areas. It showed a trend toward a similar reduction in limbic structures. But the drug did not have an effect in the extrapyramidal system at this dose. While, at a higher dose, raclopride (10.0 mg/kg), significantly reduced regional glucose metabolism throughout the susceptible grey matter areas of the brain including extrapyramidal regions, an effect similar to haloperidol. Based on approximate antipsychotic dose equivalence between haloperidol and raclopride, the clinically relevant low dose used in this study, failed to functionally alter metabolism in motor regions of brain while exerting a haloperidol-like effect in other areas traditionally linked to cognitive and affective behaviors. This suggests that a low dose of raclopride can exert regionally selective actions. The high dose of raclopride is metabolically active in all brain areas, and, therefore, in clinical application might produce involuntary motor syndromes, like parkinsonism and late onset dyskinesias, along with its antipsychotic effects.

Regional cerebral glucose metabolism compared in rodents and humans

In order to compare regional brain glucose metabolism in rats and humans, this parameter was measured using Sokoloff's deoxyglucose method in rats, and positron emission tomography with magnetic resonance imaging in humans. An atlas of cerebral regions of interest common to both species was developed to facilitate the evaluation of the relationship in regional values. We found among the regions studied a significant positive correlation in their metabolic values (r = 0.72, P < 0.001) and coefficients of variation (r = 0.59, P < 0.01) suggesting that regional brain glucose consumption is comparable between rat and human. Results of this study support the view that rat and human brain may be phylogenetically linked functionally as well as anatomically.

The effect of scopolamine on local glucose metabolism in rat brain

The effects of the muscarinic acetylcholine inhibitor scopolamine on local cerebral glucose metabolism (LCMRG) was examined. Scopolamine, 0.4 mg/kg, was injected intravenously into male Wistar rats 25 min prior to metabolic studies. The autoradiographic [ 14C]2-deoxyglucose technique was used to measure LCMRG in 5 experimental and 5 control animals. An analysis of variance was performed to test for significant regional differences. The following decreases in LCMRG expressed as a percentage change from control values were observed. The greatest decrease occurred in the globus pallidus (57.5%, P < 0.005) while the caudate nucleus only decreased to 82.6% ( P < 0.05). This may correlate with proposed cholinergic extrapyramidal pathways. Ammons Horn of hippocampus decreased to 61.1% ( P < 0.005) and the dentate gyrus to 71.8% ( P < 0.005). These are proposed cholinergic limbic pathways from the septal nuclei. The marked effect on Ammons Horn may also relate to the specific impairment of recent memory induced by scopolamine. The auditory (67.3%), frontal (70.7%) and parietal cortex (70.1%) and the lateral thalamus (73.1%) were all significantly depressed ( P < 0.005), which may be related to the proposed role of cholinergic pathways in the reticular activating system. Changes in the limbic structures including the hypothalamus (75.0%, P < 0.01), mamillary body (75.1%, P < 0.01), septal nuclei (80.5%, P < 0.05) and nucleus accumbens (89.0%, P > 0.05) were not as marked. Brain stem and cerebellar structures were not significantly affected.

Effect of administration of 5-hydroxytryptophan and an inhibitor ofl-aromatic amino acid decarboxylase on glucose metabolism in rat brain

The effect of 5-hydroxytryptophan (5-HTP)--the precursor of serotonin (5-hydroxytryptamine, 5-HT)--and of an inhibitor, N-(DL-seryl)-N'-(2,3,4-trihydroxybenzyl)hydrazine (Ro4-4602), of L-aromatic amino acid decarboxylase on the metabolism of glucose to amino acids in brain tissue was investigated. Labeled glucose (20 muCi, 0.24 mg in 0.2 ml 0.9% saline) was injected intravenously into fed rats pretreated with Ro4-4602 (50 mg/kg intraperitoneally) either alone or in combination with 5-HTP (30 mg/kg intravenously) or with the appropriate vehicle. After the injection of Ro4-4602 plus 5-HTP, the concentrations of 5-HT and 5-HTP in brain were increased, but the increase of 5-HTP was more pronounced and prolonged than the increase in 5-HT. This suggested that Ro4-4602 slightly inhibits the reaction of decarboxylation in the brain, although at the dose used the drug is usually considered to act only peripherally. After administration of Ro4-4602 alone or combined with 5-HTP, the concentration of glucose in plasma was not significantly increased. However, the concentration of glucose in brain was markedly increased with such treatments. The administration of Ro4-4602 alone or combined with 5-HTP reduced the flux of 14C from labeled glucose to amino acids in brain. The concentrations of amino acids in brain were little changed by these treatments.

Effect of dihydroxyphenylalanine administered with a monoamine oxidase inhibitor on glucose metabolism in rat brain

Injection of l-3,4-dihydroxyphenylalanine ( l-dopa) without and with an inhibitor (β-phenylisopropylhydrazine; JB516) of the enzyme, EC 1.4.3.4 monoamine: oxygen oxidoreductase (deaminating), induced hyperglycemia in fed, but not in fasted, rats. The rates of entry into and of removal of glucose from the glucose space were higher in fed rats treated with l-dopa and JB516 than in control rats. Thus, uptake of glucose by peripheral tissues is increased after treatment with l-dopa and JB516. Concentrations of glucose in brain were higher in rats treated with l-dopa and JB516 than in control rats, but uptakes of glucose- 14C by brain were not meaningfully different in controls and treated rats. At 15 min after a pulse injection of glucose- 14C, flux of 14C into lactate and alanine in brain was the same in control rats as in rats treated with l-dopa and JB516; the flux of 14C into glutamate, glutamine, aspartate, and γ-aminobutyric acid was markedly decreased in the treated rats. It is concluded that dopa injected after a monoamine oxidase inhibitor inhibits the metabolism, in brain, of glucose to the tricarboxylic acid cycle intermediates. The accumulation of unmetabolized glucose in brain in the treated rats suggests a second point of inhibition, possibly at the formation of glucose 6-phosphate.