In vivo glucose metabolism and glutamate levels in mGluR5 knockout mice: a multimodal neuroimaging study using [18F]FDG microPET and MRS

Abstract Background Perturbed functional coupling between the metabotropic glutamate receptor-5 (mGluR5) and N-methyl-d-aspartate (NMDA) receptor-mediated excitatory glutamatergic neurotransmission may contribute to the pathophysiology of psychiatric disorders such as schizophrenia. We aimed to establish the functional interaction between mGluR5 and NMDA receptors in brain of mice with genetic ablation of the mGluR5. Methods We first measured the brain glutamate levels with magnetic resonance spectroscopy (MRS) in mGluR5 knockout (KO) and wild-type (WT) mice. Then, we assessed brain glucose metabolism with [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography before and after the acute administration of an NMDA antagonist, MK-801 (0.5 mg/kg), in the same mGluR5 KO and WT mice. Results Between-group comparisons showed no significant differences in [18F]FDG standardized uptake values (SUVs) in brain of mGluR5 KO and WT mice at baseline, but widespread reductions in mGluR5 KO mice compared to WT mice after MK-801 administration (p < 0.05). The baseline glutamate levels did not differ significantly between the two groups. However, there were significant negative correlations between baseline prefrontal glutamate levels and regional [18F]FDG SUVs in mGluR5 KO mice (p < 0.05), but no such correlations in WT mice. Fisher’s Z-transformation analysis revealed significant between-group differences in these correlations (p < 0.05). Conclusions This is the first multimodal neuroimaging study in mGluR5 KO mice and the first report on the association between cerebral glucose metabolism and glutamate levels in living rodents. The results indicate that mGluR5 KO mice respond to NMDA antagonism with reduced cerebral glucose metabolism, suggesting that mGluR5 transmission normally moderates the net effects of NMDA receptor antagonism on neuronal activity. The negative correlation between glutamate levels and glucose metabolism in mGluR5 KO mice at baseline may suggest an unmasking of an inhibitory component of the glutamatergic regulation of neuronal energy metabolism.

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Effect of Acute Hypoglycemia on Human Cerebral Glucose Metabolism Measured by 13C Magnetic Resonance Spectroscopy

Diabetes ◽

10.2337/db10-1592 ◽

2011 ◽

Vol 60 (5) ◽

pp. 1467-1473 ◽

Cited By ~ 22

Author(s):

K. C. C. van de Ven ◽

B. E. de Galan ◽

M. van der Graaf ◽

A. A. Shestov ◽

P.-G. Henry ◽

...

Keyword(s):

Magnetic Resonance ◽

Glucose Metabolism ◽

Magnetic Resonance Spectroscopy ◽

Cerebral Glucose Metabolism ◽

Resonance Spectroscopy ◽

13C Magnetic Resonance Spectroscopy ◽

Acute Hypoglycemia

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Lack of effect of L-687,414 ((+)-cis-4-methyl-HA-966)5 an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology

British Journal of Pharmacology ◽

10.1111/j.1476-5381.1993.tb13768.x ◽

1993 ◽

Vol 110 (1) ◽

pp. 36-42 ◽

Cited By ~ 76

Author(s):

R.J. Hargreaves ◽

M. Rigby ◽

D. Smith ◽

R.G. Hill

Keyword(s):

Nmda Receptor ◽

Glucose Metabolism ◽

Receptor Antagonist ◽

Nmda Receptor Antagonist ◽

Neuronal Morphology ◽

Cerebral Glucose Metabolism ◽

Glycine Site

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Altered 13C Glucose Metabolism in the Cortico—Striato—Thalamo—Cortical Loop in the MK-801 Rat Model of Schizophrenia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.193 ◽

2010 ◽

Vol 31 (3) ◽

pp. 976-985 ◽

Cited By ~ 17

Author(s):

Elvar M Eyjolfsson ◽

Linn Hege Nilsen ◽

Daniel Kondziella ◽

Eiliv Brenner ◽

Asta Håberg ◽

...

Keyword(s):

Nmda Receptor ◽

High Performance ◽

Temporal Cortex ◽

Gas Chromatography Mass Spectrometry ◽

Resonance Spectroscopy ◽

Dopamine Turnover ◽

Mk 801 ◽

Pronounced Reduction ◽

Monoaminergic Neurotransmitter ◽

Synthesis And Degradation

Using a modified MK-801 (dizocilpine) N-methyl-d-aspartic acid (NMDA) receptor hypofunction model for schizophrenia, we analyzed glycolysis, as well as glutamatergic, GABAergic, and monoaminergic neurotransmitter synthesis and degradation. Rats received an injection of MK-801 daily for 6 days and on day 6, they also received an injection of [1-13C]glucose. Extracts of frontal cortex (FCX), parietal and temporal cortex (PTCX), thalamus, striatum, nucleus accumbens (NAc), and hippocampus were analyzed using 13C nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, and gas chromatography—mass spectrometry. A pronounced reduction in glycolysis was found only in PTCX, in which 13C labeling of glucose, lactate, and alanine was decreased. 13C enrichment in lactate, however, was reduced in all areas investigated. The largest reductions in glutamate labeling were detected in FCX and PTCX, whereas in hippocampus, striatum, and Nac, 13C labeling of glutamate was only slightly but significantly reduced. The thalamus was the only region with unaffected glutamate labeling. γ-Aminobutyric acid (GABA) labeling was reduced in all areas, but most significantly in FCX. Glutamine and aspartate labeling was unchanged. Mitochondrial metabolites were also affected. Fumarate labeling was reduced in FCX and thalamus, whereas malate labeling was reduced in FCX, PTCX, striatum, and NAc. Dopamine turnover was decreased in FCX and thalamus, whereas that of serotonin was unchanged in all regions. In conclusion, neurotransmitter metabolism in the cortico—striato—thalamo—cortical loop is severely impaired in the MK-801 (dizocilpine) NMDA receptor hypofunction animal model for schizophrenia.

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Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: role of N-methyl-d-aspartate and opioid receptors

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2015-0429 ◽

2016 ◽

Vol 94 (6) ◽

pp. 599-612 ◽

Cited By ~ 26

Author(s):

Arya Haj-Mirzaian ◽

Nastaran Kordjazy ◽

Sattar Ostadhadi ◽

Shayan Amiri ◽

Arvin Haj-Mirzaian ◽

...

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Receptor Antagonist ◽

Opioid Receptor ◽

Receptor Agonist ◽

Physical Stress ◽

Acute Administration ◽

Mk 801 ◽

Behavioral Despair ◽

Immobility Time

Opioid and N-methyl-d-aspartate (NMDA) receptors mediate different effects of fluoxetine. We investigated whether opioid and NMDA receptors are involved in the protective effect of fluoxetine against the behavioral despair induced by acute physical stress in male mice. We used the forced swimming test (FST), tail suspension test (TST), and open-field test (OFT) for behavioral evaluation. We used fluoxetine, naltrexone (opioid receptor antagonist), MK-801 (NMDA receptor antagonist), morphine (opioid receptor agonist), and NMDA (NMDA receptor agonist). Acute foot-shock stress (FSS) significantly induced behavioral despair (depressive-like) and anxiety-like behaviors in tests. Fluoxetine (5 mg/kg) reversed the depressant-like effect of FSS, but it did not alter the locomotion and anxiety-like behavior in animals. Acute administration of subeffective doses of naltrexone (0.3 mg/kg) or MK-801 (0.01 mg/kg) potentiated the antidepressant-like effect of fluoxetine, while subeffective doses of morphine (1 mg/kg) and NMDA (75 mg/kg) abolished this effect of fluoxetine. Also, co-administration of subeffective doses of naltrexone (0.05 mg/kg) and MK-801 (0.003 mg/kg) with fluoxetine (1 mg/kg) induced a significant decrease in the immobility time in FST and TST. Our results showed that opioid and NMDA receptors (alone or in combination) are involved in the antidepressant-like effect of fluoxetine against physical stress.

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Alkalemia reduces recovery from global cerebral ischemia by NMDA receptor-mediated mechanism

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.6.h2557 ◽

1997 ◽

Vol 272 (6) ◽

pp. H2557-H2562

Author(s):

P. D. Hurn ◽

R. C. Koehler ◽

R. J. Traystman

Keyword(s):

Energy Metabolism ◽

Cerebral Ischemia ◽

Nmda Receptor ◽

Nmda Receptor Antagonist ◽

Global Cerebral Ischemia ◽

Resonance Spectroscopy ◽

Mk 801 ◽

Sagittal Sinus

In vitro data suggest that low tissue pH reduces, whereas extracellular alkalosis potentiates, cerebral anoxic injury via excitotoxic mechanisms. We tested the hypothesis that in vivo metabolic alkalemia potentiates defects in energy metabolism after global incomplete cerebral ischemia (12 min) and reperfusion (180 min) by an N-methyl-D-aspartate (NMDA) receptor-mediated mechanism. Brain ATP, phosphocreatine, and intracellular pH (pHi) were measured by 31P magnetic resonance spectroscopy in anesthetized dogs treated with 1) preischemic intravenous carbicarb buffer (NaHCO3+Na2CO3, Carb, n = 7); 2) carbicarb infusion plus NMDA receptor antagonist MK-801 (MK-801 + Carb, n = 7); 3) an osmotically equivalent volume of 5% NaCl (NaCl, n = 8); or 4) equivalent volume of 0.9% NaCl (Sal, n = 3). Sagittal sinus pH was raised to 7.82 +/- 0.04 before and 7.65 +/- 0.03 during ischemia in Carb vs. 7.72 +/- 0.01 and 7.60 +/- 0.01 in MK-801+Carb, 7.25 +/- 0.02 and 7.15 +/- 0.03 in NaCl, and 7.31 +/- 0.00 and 7.26 +/- 0.01 in Sal, respectively. Ischemic cerebral blood flow (CBF, radiolabeled microspheres), pHi, and ATP reduction were similar among groups. By 180 min of reperfusion, recovery of ATP was greater in MK-801+Carb (104 +/- 6% of baseline), NaCl (93 +/- 6%), and Sal (94 +/- 6%) than in Carb (47 +/- 6%). Intraischemic pHi was similar among groups, and pHi recovery did not vary among groups despite differences in sagittal sinus pH. In Carb, CBF was restored but with delayed hypoperfusion. We conclude that extracellular alkalosis is deleterious to postischemic CBF and energy metabolism, acting by NMDA receptor-mediated mechanisms.

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