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Abstract:
Objective
Based on the growing evidence for imbalance with regard to glutamatergic (Glu) neurotransmission in major depressive disorder (MDD), this study aims at establishing a multimodal imaging approach for the investigation of Glu-neurometabolism (magnetic resonance spectroscopy, 1H-MRS) and metabotropic glutamate receptor (mGluR5) densities (positron emission tomography, PET), in order to provide insight into the neuropharmacological effects of ketamine and the biomechanisms of its antidepressant potential.
Method
20 healthy subjects completed two separate imaging sessions including 11C-ABP688-PET to quantify mGluR5 densities and 1H-MRS to quantify mean metabolite levels in the anterior cingulate cortex. Before PET scanning, either placebo or S-ketamine (i.v. bolus of 0.12 mg/kg, infusion of 0.25 mg/kg/h over 40 min) was administered in a double-blind randomized manner.
Results
For the first time, we evaluate a multimodal PET-MR imaging approach for the investigation of glutamate-dependent neuroreceptor plasticity in vivo. 11C-ABP688 is a PET ligand that binds to an allosteric site on the mGluR5 with high specificity and thus enables the investigation of e.g. glutamate-dependent receptor internalization after ketamine challenge. We present the first in vivo data on the relationship between ketamine induced changes in Glu-metabolism and post-challenge mGluR5 densities, extending recent preclinical evidence on the effects of ketamine on Glu-signaling and cerebral neuroenergetics.
Conclusion
Since the interaction between neurotransmitters and receptors is expected to drive the dynamics of receptor expression, a better knowledge of the molecular mechanisms underlying such functional coupling between neurotransmitter and receptor is crucial for the understanding of synaptic plasticity in health and disease. Multimodal and molecular imaging techniques are promising approaches for the in vivo investigation of these processes in humans and animals, and offer powerful tools for neuropsychiatric research such as investigation of the rapid antidepressant response to ketamine.
