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Abstract:
Background: Recent findings highlight the role of glutamate-driven synaptic plasticity in the therapeutic action of psychedelic drugs such as ketamine. Since metabotropic glutamate receptors 5 (mGluR5) interact closely with NMDA
receptors and play an important role in the modulation of glutamatergic signalling, we assessed glutamate-dependent mGluR5 plasticity following ketamine-induced NMDA-R antagonism using a multimodal PET-MRS imaging approach.
Methods: We quantified mGluR5 densities using 11C-ABP688-PET and glutamate levels in the pregenual anterior cingulate cortex (PACC) using 1H-MRS in 20 healthy subjects. Before 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 doubleblind randomized manner.
Results: Post-infusion glutamate levels and mGluR5 densities were highly correlated in the PACC following ketamine challenge but did not show any significant relation under placebo conditions. Anterior cingulate mGluR5 densities predicted psychedelic alterations of consciousness during ketamine infusion.
Conclusions: To our knowledge, this is the first double-blind, randomized, placebo-controlled PET-MRS study that reports a pharmacological modulation of glutamate-dependent mGluR5 plasticity in vivo. Our findings complement previous reports of increased glutamate release during ketamine challenge by providing additional evidence for glutamate-mGluR5 coupling. Specifically, we raise the hypothesis that mGluR5 might play a critical role in mediating ketamineinduced alterations of consciousness as part of its therapeutic action.
