NMDA receptor ion channel activation detected in vivo with [18F]GE-179 PET after electrical stimulation of rat hippocampus

Author:

Vibholm Ali K1ORCID,Landau Anne M12ORCID,Møller Arne13,Jacobsen Jan1,Vang Kim1,Munk Ole L1,Orlowski Dariusz4,Sørensen Jens CH4,Brooks David J15

Affiliation:

1. Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark

2. Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark

3. Centre of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark

4. Department of Neurosurgery and CENSE, Aarhus University Hospital, Aarhus, Denmark

5. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

Abstract

The positron emission tomography (PET) tracer [18F]GE-179 binds to the phencyclidine (PCP) site in the open N-methyl-D-aspartate receptor ion channel (NMDAR-IC). To demonstrate that PET can visualise increased [18F]GE-179 uptake by active NMDAR-ICs and that this can be blocked by the PCP antagonist S-ketamine, 15 rats had an electrode unilaterally implanted in their ventral hippocampus. Seven rats had no stimulation, five received pulsed 400 µA supra-threshold 60 Hz stimulation alone, and three received intravenous S-ketamine injection prior to stimulation. Six other rats were not implanted. Each rat had a 90 min [18F]GE-179 PET scan. Stimulated rats had simultaneous depth-EEG recordings of induced seizure activity. [18F]GE-179 uptake (volume of distribution, VT) was compared between hemispheres and between groups. Electrical stimulation induced a significant increase in [18F]GE-179 uptake at the electrode site compared to the contralateral hippocampus (mean 22% increase in VT, p =  0.0014) and to non-stimulated comparator groups. Rats injected with S-ketamine prior to stimulation maintained non-stimulated levels of [18F]GE-179 uptake during stimulation. In conclusion, PET visualisation of focal [18F]GE-179 uptake during electrically activated NMDAR-ICs and the demonstration of specificity for PCP sites by blockade with S-ketamine support the in vivo utility of [18F]GE-179 PET as a use-dependent marker of NMDAR-IC activation.

Publisher

SAGE Publications

Subject

Cardiology and Cardiovascular Medicine,Clinical Neurology,Neurology

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