Glutamate and Glutamine Measured With 4.0 T Proton MRS in Never-Treated Patients With Schizophrenia and Healthy Volunteers

Théberge, Jean; Bartha, Robert; Drost, Dick J.; Menon, Ravi S.; Malla, Ashok; Takhar, Jatinder; Neufeld, Richard W. J.; Rogers, John; Pavlosky, William; Schaefer, Betsy; Densmore, Maria; Al-Semaan, Yousef; Williamson, Peter C.

doi:10.1176/appi.ajp.159.11.1944

Cited by 378 publications

(342 citation statements)

References 11 publications

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“…Consequently, thalamic filter function is impaired. If glutamatergic NMDA receptors are dysfunctional in schizophrenia, the present and other studies suggest that secondary disturbances in glial-neuronal interactions and the glutamine-glutamate cycle may occur in this disorder (Do et al, 2000;Theberge et al, 2002Theberge et al, , 2003. This may then contribute to imbalance of the cortico-striato-thalamocortical feedback as also suggested by Laruelle et al (2003).…”

Section: Dopamine and Its Interaction With Glutamate Metabolismsupporting

confidence: 71%

“…As pointed out in the Introduction, glutamate and glutamine are very closely linked metabolically. In an in vivo 1 H NMRS study it was suggested that the glutamine signal in spectra of anterior cingulate and thalamus of drugnaive first episode schizophrenia patients was increased compared to age-matched healthy controls (Theberge et al, 2002). However, using 1 H NMRS at low field strength it is not possible to fully separate glutamate and glutamine signals, whereas there is no overlap between these two amino-acid signals using high field 1 H NMRS or HPLC.…”

Section: Glutamate-glutamine-gaba Cycle and Glial-neuronal Interactionsmentioning

confidence: 99%

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Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Kondziella

Brenner

Eyjolfsson

et al. 2005

Neuropsychopharmacol

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Schizophrenia-mimicking compounds such as phencyclidine (PCP) and MK801 are antagonists at the N-methyl-D-aspartate (NMDA) receptor and produce the whole spectrum of positive, negative, and cognitive symptoms. This is one of the most important pillars of the hypoglutamatergic hypothesis of schizophrenia. Since the synthesis of glutamate and GABA in neurons is closely connected to astrocyte metabolism, the study of astrocytic function is essential in this context. Dizocilpine-maleate (MK801) (0.5 mg/kg) was injected into rats every day for 6 days. The last dose was given together with [1-13 C]glucose and [1,2-13 C]acetate. Extracts from frontal, retrosplenial, and cingulate cortices (CRFC) and temporal lobes were examined by 13 C nuclear magnetic resonance spectroscopy, high pressure liquid chromatography, and light microscopy. In CRFC, significant increases in the levels of glutamate, glutathione, and taurine were seen, whereas amounts and turnover of noradrenaline, dopamine, and serotonin were unchanged. Glutamate and glutamine, derived from [1,2-13 C]acetate and thus astrocytes, were significantly decreased in CRFC as compared to controls. Labeling from [1-13 C]glucose and thus mostly neuronal metabolism was affected in the same brain region with decreased labeling of glutamate and GABA. The present model mimics the increased glutamate/glutamine activity found in drug-naive patients with first episode schizophrenia. Moreover, the decreased labeling indicates the transition to lower glutamatergic function seen in chronic schizophrenia patients. The disturbance in astrocytic function and the glutamine-glutamate-GABA cycle are of significant importance and might add to the malfunction of the cortico-striato-thalamo-cortical loop caused by NDMA receptor blockade.

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Section: Dopamine and Its Interaction With Glutamate Metabolismsupporting

confidence: 71%

Section: Glutamate-glutamine-gaba Cycle and Glial-neuronal Interactionsmentioning

confidence: 99%

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Kondziella

Brenner

Eyjolfsson

et al. 2005

Neuropsychopharmacol

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“…An antagonism at this location could, in turn, cause regional hypermetabolism from increased glutamate release (Gluck et al, 2002;Theberge et al, 2002;Bartha et al, 1997;Moghaddam et al, 1997;Moghaddam and Adams, 1998). The mechanism for this phenomenon may be attributed to disinhibition of inhibitory interneurons in the anterior thalamus, basal forebrain, or frontal cortex (Farber, 2003;Carter et al, 2004;Tomitaka et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

Holcomb

Lahti

Medoff

et al. 2005

Neuropsychopharmacol

101

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Schizophrenia may be related to dysfunctional glutamatergic activity, specifically hypofunction of the N-methyl-D-aspartate receptor (NMDAR). In addition, it has been proposed that NMDAR hypofunction may paradoxically cause an increase in glutamate release and hypermetabolism in corticolimbic regions. If a state of partial, chronic NMDAR blockade underlies schizophrenia, then schizophrenic volunteers (SV) may have greater glutamate release and associated elevations in regional cerebral blood flow (rCBF) than normal volunteers (NV), following drug-induced NMDAR antagonism. Therefore, we have given acute ketamine, a noncompetitive NMDAR antagonist, to NV (n ¼ 13) and medicated volunteers with schizophrenia (n ¼ 10) in conjunction with serial positron emission tomography blood flow studies. Drug administration caused marked rCBF elevations in frontal and cingulate regions in both groups. Contrasts between NV and SV ketamine groups showed that SV had greater relative blood flow increases in the anterior cingulate than NV. Maximum blood flow, and the area under the curve for blood flow in the anterior cingulate cortex, significantly correlated with changes in psychosis ratings in SV and NV (maximum rCBF only). These changes are consistent with a relatively hypoactive thalamic NMDAR and increased cortical glutamate neurotransmission at non-NMDARs in schizophrenia. We hypothesize that ketamine antagonizes an NMDAR-dependent inhibitory system that is partially compromised in subjects with schizophrenia. The ketamine-induced reduction of inhibition leads to a marked increase in glutamate release and hypermetabolism (elevated rCBF) in frontal and cingulate cortical regions. The loss of inhibition and increased glutamate release may cause the distorted thoughts and diminished cognitive abilities elicited by NMDAR blockade.

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“…Complementary with that finding is a study at 3 T that showed elevated glutamate/glutamine in adolescents who were at high risk for schizophrenia (69). In a more recent study, the same group at a magnetic field strength of 4 T reported that the increase is, in fact, glutamine, without a concomitant change in glutamate (70). Little else has been reported for glutamate, glutamine and GABA in schizophrenia with MRS. At 4 T, the spectral resolution is adequate to differentiate the glutamate and glutamine, but a cautionary note is that, at the 20 ms echo delay used in this study, macromolecules are a significant contaminant of the glutamate and glutamine peaks.…”

Section: Glutamate Glutamine and Gabamentioning

confidence: 87%

MR spectroscopy: its potential role for drug development for the treatment of psychiatric diseases

Mason

Krystal

2006

NMR Biomed.

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Magnetic resonance spectroscopy (MRS) is likely in the near future to play a key role in the process of drug discovery and evaluation. As the pharmaceutical industry seeks biochemical markers of drug delivery, efficacy and toxicity, this non-invasive technique offers numerous ways to study adults and children repeatedly and without ionizing radiation. In this article, we survey an array of the information that MRS offers about neurochemistry in general and psychiatric disorders and their treatment in particular. We also present growing evidence of glial abnormalities in neuropsychiatric disorders and discuss what MRS is contributing to that line of investigation. The third major direction of this article is the discussion of where MRS techniques are headed and how those new techniques can contribute to studies of mechanisms of psychiatric disease and drug discovery.

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Glutamate and Glutamine Measured With 4.0 T Proton MRS in Never-Treated Patients With Schizophrenia and Healthy Volunteers

Cited by 378 publications

References 11 publications

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

MR spectroscopy: its potential role for drug development for the treatment of psychiatric diseases

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