Effects of Ketamine on Anterior Cingulate Glutamate Metabolism in Healthy Humans: A 4-T Proton MRS Study

Rowland, Laura M.; Bustillo, Juan; Mullins, Paul G.; Jung, Rex E.; Lenroot, Rhoshel; Landgraf, Elma; Barrow, Ranee; Yeo, Ronald A.; Lauriello, John; Brooks, William M.

doi:10.1176/appi.ajp.162.2.394

Cited by 277 publications

(197 citation statements)

References 16 publications

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“…This is in accordance with the findings in human schizophrenia patients (Stanley et al, 1996;Theberge et al, 2003;Ohrmann et al, 2005) and healthy subjects exposed to ketamine (Rowland et al, 2005). Thus, the repeated administration might generate a better schizophrenia model than acute exposure and emphasizes the importance of the frontal and retrosplenial/cingulate cortex for the pathophysiology of schizophrenia.…”

Section: Effects Of Repeated Mk801 On Metabolism D Kondziella Et Alsupporting

confidence: 90%

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: Effects Of Repeated Mk801 On Metabolism D Kondziella Et Alsupporting

confidence: 90%

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

Kondziella

Brenner

Eyjolfsson

et al. 2005

Neuropsychopharmacol

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“…Although ketamine induces NMDA receptor hypofunction, acute ketamine leads to increased glutamate in the extracellular space in animals (Moghaddam et al, 1997) and increased glutamate in humans as measured by magnetic resonance spectroscopy (Rowland et al, 2005). Glutamate level is reduced in chronic schizophrenia (Theberge et al, 2003;Ohrmann et al, 2005Ohrmann et al, , 2007 but increased in early psychosis (Theberge et al, 2002;Bartha et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Gamma and Delta Neural Oscillations and Association with Clinical Symptoms under Subanesthetic Ketamine

Hong

Summerfelt

Boyer

et al. 2009

Neuropsychopharmacol

255

151

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Several electrical neural oscillatory abnormalities have been associated with schizophrenia, although the underlying mechanisms of these oscillatory problems are unclear. Animal studies suggest that one of the key mechanisms of neural oscillations is through glutamatergic regulation; therefore, neural oscillations may provide a valuable animal-clinical interface on studying glutamatergic dysfunction in schizophrenia. To identify glutamatergic control of neural oscillation relevant to human subjects, we studied the effects of ketamine, an N-methyl-D-aspartate antagonist that can mimic some clinical aspects of schizophrenia, on auditory-evoked neural oscillations using a paired-click paradigm. This was a double-blind, placebo-controlled, crossover study of ketamine vs saline infusion on 10 healthy subjects. Clinically, infusion of ketamine in subanesthetic dose significantly increased thought disorder, withdrawal-retardation, and dissociative symptoms. Ketamine significantly augmented high-frequency oscillations (gamma band at 40-85 Hz, p ¼ 0.006) and reduced lowfrequency oscillations (delta band at 1-5 Hz, po0.001) compared with placebo. Importantly, the combined effect of increased gamma and reduced delta frequency oscillations was significantly associated with more withdrawal-retardation symptoms experienced during ketamine administration (p ¼ 0.02). Ketamine also reduced gating of the theta-alpha (5-12 Hz) range oscillation, an effect that mimics previously described deficits in schizophrenia patients and their first-degree relatives. In conclusion, acute ketamine appeared to mimic some aspects of neural oscillatory deficits in schizophrenia, and showed an opposite effect on scalp-recorded gamma vs low-frequency oscillations. These electrical oscillatory indexes of subanesthetic ketamine can be potentially used to cross-examine glutamatergic pharmacological effects in translational animal and human studies.

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“…The one study that induced NMDA blockade in humans found increased Gln in the anterior cingulate. 76 Rowland et al used 1 H MRS to measure Gln levels, thus, indirectly assessing Glu neurotransmitter release. In contrast, our results indicated less Glu across the regions of interest in both twins with schizophrenia and their unaffected co-twins compared with controls.…”

Section: Discussionmentioning

confidence: 99%

Proton MRS in twin pairs discordant for schizophrenia

et al. 2008

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Proton magnetic resonance spectroscopy ( 1 H MRS) neurometabolite abnormalities have been detected widely in subjects with and at risk for schizophrenia. We hypothesized that such abnormalities would be present both in patients with schizophrenia and in their unaffected twin siblings. We acquired magnetic resonance spectra (TR/TE = 3000/30 ms) at voxels in the mesial prefrontal gray matter, left prefrontal white matter and left hippocampus in 14 twin pairs discordant for schizophrenia (2 monozygotic, 12 dizygotic), 13 healthy twin pairs (4 monozygotic, 9 dizygotic) and 1 additional unaffected co-twin of a schizophrenia proband. In the mesial prefrontal gray matter voxel, N-acetylaspartate (NAA), creatine þ phosphocreatine (Cr), glycerophosphocholine þ phosphocholine (Cho) and myo-inositol (mI) did not differ significantly between patients with schizophrenia, their unaffected co-twins or healthy controls. However, glutamate (Glu) was significantly lower in patients with schizophrenia (31%, percent difference) and unaffected co-twins (21%) than in healthy controls (collapsed across twin pairs). In the left hippocampus voxel, levels of NAA (23%), Cr (22%) and Cho (36%) were higher in schizophrenia patients compared with controls. Hippocampal NAA (25%), Cr (22%) and Cho (37%) were also significantly higher in patients than in their unaffected co-twins. Region-to-region differences in metabolite levels were also notable within all three diagnosis groups. These findings suggest that 1 H MRS neurometabolite abnormalities are present not only in patients with schizophrenia, but also in their unaffected co-twins. Thus, reduced mesial prefrontal cortical Glu and elevated hippocampal NAA, Cr and Cho may represent trait markers of schizophrenia risk and, when exacerbated, state markers of schizophrenia itself.

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Effects of Ketamine on Anterior Cingulate Glutamate Metabolism in Healthy Humans: A 4-T Proton MRS Study

Abstract: In humans as in animals, an acute hypofunctional NMDAR state is associated with increased glutamatergic activity in the anterior cingulate.

Cited by 277 publications

References 16 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

Gamma and Delta Neural Oscillations and Association with Clinical Symptoms under Subanesthetic Ketamine

Proton MRS in twin pairs discordant for schizophrenia

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