Christine DeLorenzo1, Nicole DellaGioia2, Michael Bloch3, Gerard Sanacora2, Nabeel Nabulsi4, Chadi Abdallah5, Jie Yang6, Ruofeng Wen7, J John Mann8, John H Krystal5, Ramin V Parsey9, Richard E Carson10, Irina Esterlis3. 1. Departments of Psychiatry, Stony Brook University, Stony Brook, New York, New York; Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, New York. Electronic address: Christine.DeLorenzo@stonybrookmedicine.edu. 2. Department of Psychiatry, Columbia University, New York, New York. 3. Department of Psychiatry, Columbia University, New York, New York; Departments of Biomedical Engineering, Yale University, New Haven; Child Study Center, Yale University, New Haven. 4. Departments of Psychiatry, Yale University, New Haven. 5. Department of Psychiatry, Columbia University, New York, New York; Departments of Biomedical Engineering, Yale University, New Haven; Clinical Neuroscience Division, National Center for PTSD, West Haven, Connecticut. 6. Departments of Radiology, Stony Brook University, Stony Brook, New York, New York. 7. Departments of Preventive Medicine, Stony Brook University, Stony Brook, New York, New York. 8. Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, New York. 9. Departments of Biomedical Engineering, Stony Brook University, Stony Brook, New York, New York. 10. Departments of Psychiatry, Yale University, New Haven; Diagnostic Radiology, Yale University, New Haven.
Abstract
BACKGROUND: At subanesthetic doses, ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, increases glutamate release. We imaged the acute effect of ketamine on brain metabotropic glutamatergic receptor subtype 5 with a high-affinity positron emission tomography (PET) ligand [(11)C]ABP688 (E)-3-[2-(6-methyl-2-pyridinyl)ethynyl]-2-cyclohexen-1-one-O-(methyl-11C)oxime, a negative allosteric modulator of the metabotropic glutamatergic receptor subtype 5. METHODS: Two [(11)C]ABP688 PET scans were performed in 10 healthy nonsmoking human volunteers (34 ± 13 years old); the two PET scans were performed on the same day-before (scan 1) and during intravenous ketamine administration (.23 mg/kg over 1 min, then .58 mg/kg over 1 hour; scan 2). The PET data were acquired for 90 min immediately after [(11)C]ABP688 bolus injection. Input functions were obtained through arterial blood sampling with metabolite analysis. RESULTS: A significant reduction in [(11)C]ABP688 volume of distribution was observed in scan 2 relative to scan 1 of 21.3% ± 21.4%, on average, in the anterior cingulate, medial prefrontal cortex, orbital prefrontal cortex, ventral striatum, parietal lobe, dorsal putamen, dorsal caudate, amygdala, and hippocampus. There was a significant increase in measurements of dissociative state after ketamine initiation (p < .05), which resolved after completion of the scan. CONCLUSIONS: This study provides first evidence that ketamine administration decreases [(11)C]ABP688 binding in vivo in human subjects. The results suggest that [(11)C]ABP688 binding is sensitive to ketamine-induced effects, although the high individual variation in ketamine response requires further examination.
BACKGROUND: At subanesthetic doses, ketamine, an N-methyl-D-aspartateglutamate receptor antagonist, increases glutamate release. We imaged the acute effect of ketamine on brain metabotropic glutamatergic receptor subtype 5 with a high-affinity positron emission tomography (PET) ligand [(11)C]ABP688 (E)-3-[2-(6-methyl-2-pyridinyl)ethynyl]-2-cyclohexen-1-one-O-(methyl-11C)oxime, a negative allosteric modulator of the metabotropic glutamatergic receptor subtype 5. METHODS: Two [(11)C]ABP688 PET scans were performed in 10 healthy nonsmoking human volunteers (34 ± 13 years old); the two PET scans were performed on the same day-before (scan 1) and during intravenous ketamine administration (.23 mg/kg over 1 min, then .58 mg/kg over 1 hour; scan 2). The PET data were acquired for 90 min immediately after [(11)C]ABP688 bolus injection. Input functions were obtained through arterial blood sampling with metabolite analysis. RESULTS: A significant reduction in [(11)C]ABP688 volume of distribution was observed in scan 2 relative to scan 1 of 21.3% ± 21.4%, on average, in the anterior cingulate, medial prefrontal cortex, orbital prefrontal cortex, ventral striatum, parietal lobe, dorsal putamen, dorsal caudate, amygdala, and hippocampus. There was a significant increase in measurements of dissociative state after ketamine initiation (p < .05), which resolved after completion of the scan. CONCLUSIONS: This study provides first evidence that ketamine administration decreases [(11)C]ABP688 binding in vivo in human subjects. The results suggest that [(11)C]ABP688 binding is sensitive to ketamine-induced effects, although the high individual variation in ketamine response requires further examination.
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