Temporal Dynamics of Antidepressant Ketamine Effects on Glutamine Cycling Follow Regional Fingerprints of AMPA and NMDA Receptor Densities.
The anterior cingulate cortex (ACC) has shown decreased glutamate levels in patients with major depressive disorder. Subanesthetic doses of ketamine were repeatedly shown to improve depressive symptoms within 24 h after infusion and this antidepressant effect was attributed to increased α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) throughput. To elucidate ketamine's mechanism of action, we tested whether the clinical time course of the improvement is mirrored by the change of glutamine/glutamate ratio and if such effects show a regional and temporal specificity in two distinct subdivisions of ACC with different AMPA/N-methyl-D-aspartate receptor profiles. In a double-blind, placebo-controlled intravenous infusion study of ketamine, we measured glutamate and glutamine in the pregenual ACC (pgACC) and the anterior midcingulate cortex at 1 and 24 h post infusion with magnetic resonance spectroscopy at 7 T. A significant interaction of time, region, and treatment was found for the glutamine/glutamate ratios (placebo, n=14; ketamine, n=12). Post-hoc analyses revealed that the glutamine/glutamate ratio increased significantly in the ketamine group, compared with placebo, specifically in the pgACC after 24 h. The glutamine/glutamate increase in the pgACC caused by ketamine at 24 h post infusion was reproduced in an enlarged sample (placebo, n=24; ketamine, n=20). Our results support a significant temporal and regional response in glutamine/glutamate ratios to a single subanesthetic dose of ketamine, which mirrors the time course of the antidepressant response and reversal of the molecular deficits in patients and which may be associated with the histoarchitectonical receptor fingerprints of the ACC subregions.
Clinical Affective Neuroimaging Laboratory, Leibniz Institute for Neurobiology, Otto von Guericke University, Magdeburg, Germany.|Department of Neurology, Otto von Guericke University, Magdeburg, Germany.
Meng
M
Li
Clinical Affective Neuroimaging Laboratory, Leibniz Institute for Neurobiology, Otto von Guericke University, Magdeburg, Germany.|Department of Neurology, Otto von Guericke University, Magdeburg, Germany.
Liliana Ramona
LR
Demenescu
Clinical Affective Neuroimaging Laboratory, Leibniz Institute for Neurobiology, Otto von Guericke University, Magdeburg, Germany.|Leibniz Institute for Neurobiology, Magdeburg, Germany.
Lejla
L
Colic
German Centre for Neurodegenerative Diseases (DZNE), Site Magdeburg, Germany.|Institute of Cognitive Neurology and Dementia Research (IKND), Magdeburg, Germany.|Centre for Behavioural Brain Sciences (CBBS), Magdeburg, Germany.|Department of Psychiatry and Psychotherapy, Otto von Guericke University, Magdeburg, Germany.
Coraline Danielle
CD
Metzger
Department of Neurology, Otto von Guericke University, Magdeburg, Germany.|Leibniz Institute for Neurobiology, Magdeburg, Germany.|Centre for Behavioural Brain Sciences (CBBS), Magdeburg, Germany.|Department of Psychiatry and Psychotherapy, Otto von Guericke University, Magdeburg, Germany.
Hans-Jochen
HJ
Heinze
Centre for Behavioural Brain Sciences (CBBS), Magdeburg, Germany.|Department of Psychiatry and Psychotherapy, Otto von Guericke University, Magdeburg, Germany.
Johann
J
Steiner
Leibniz Institute for Neurobiology, Magdeburg, Germany.|German Centre for Neurodegenerative Diseases (DZNE), Site Magdeburg, Germany.|Centre for Behavioural Brain Sciences (CBBS), Magdeburg, Germany.|Department of Biomedical Magnetic Resonance, Otto von Guericke University, Magdeburg, Germany.
Oliver
O
Speck
Leibniz Institute for Neurobiology, Magdeburg, Germany.|Centre for Behavioural Brain Sciences (CBBS), Magdeburg, Germany.|Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Anna
A
Fejtova
Janssen Research and Development, Titusville, NJ, USA.
Giacomo
G
Salvadore
Clinical Affective Neuroimaging Laboratory, Leibniz Institute for Neurobiology, Otto von Guericke University, Magdeburg, Germany.|Leibniz Institute for Neurobiology, Magdeburg, Germany.|Centre for Behavioural Brain Sciences (CBBS), Magdeburg, Germany.|Department of Psychiatry and Psychotherapy, Otto von Guericke University, Magdeburg, Germany.|Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
Martin
M
Walter
D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism*; D005973:Glutamine / Q000187:drug effects / Q000378:metabolism*; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D055815:Young Adult
D000928:Antidepressive Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D005973:Glutamine; D018698:Glutamic Acid; D007649:Ketamine