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In vivo brain endocannabinoid metabolism is related to hippocampus glutamate and structure – a multimodal imaging study with PET, 1H-MRS, and MRI

Abstract

Dysregulation of hippocampus glutamatergic neurotransmission and reductions in hippocampal volume have been associated with psychiatric disorders. The endocannabinoid system modulates glutamate neurotransmission and brain development, including hippocampal remodeling. In humans, elevated levels of anandamide and lower activity of its catabolic enzyme fatty acid amide hydrolase (FAAH) are associated with schizophrenia diagnosis and psychotic symptom severity, respectively (Neuropsychopharmacol, 29(11), 2108–2114; Biol. Psychiatry 88 (9), 727–735). Although preclinical studies provide strong evidence linking anandamide and FAAH to hippocampus neurotransmission and structure, these relationships remain poorly understood in humans. We recruited young adults with and without psychotic disorders and measured FAAH activity, hippocampal glutamate and glutamine (Glx), and hippocampal volume using [11C]CURB positron emission tomography (PET), proton magnetic resonance spectroscopy (1H-MRS) and T1-weighted structural MRI, respectively. We hypothesized that higher FAAH activity would be associated with greater hippocampus Glx and lower hippocampus volume, and that these effects would differ in patients with psychotic disorders relative to healthy control participants. After attrition and quality control, a total of 37 participants (62% male) completed [11C]CURB PET and 1H-MRS of the left hippocampus, and 45 (69% male) completed [11C]CURB PET and hippocampal volumetry. Higher FAAH activity was associated with greater concentration of hippocampal Glx (F1,36.36 = 9.17, p = 0.0045; Cohen’s f = 0.30, medium effect size) and smaller hippocampal volume (F1,44.70 = 5.94, p = 0.019, Cohen’s f = 0.26, medium effect size). These effects did not differ between psychosis and healthy control groups (no group interaction). This multimodal imaging study provides the first in vivo evidence linking hippocampal Glx and hippocampus volume with endocannabinoid metabolism in the human brain.

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Fig. 1: Hippocampus voxel placement and 1H-MRS spectrum.
Fig. 2: Associations of hippocampus Glx with regional [11C]CURB λk3.
Fig. 3: Associations of hippocampus volume with regional [11C]CURB λk3.

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Acknowledgements

The authors would like to thank the members of the Neuroimaging in Early Psychosis laboratory for their contributions toward data collection, the staff of the CAMH Research Imaging Centre, and Marcos Sanches for biostatistical support and advice.

Funding

This work was supported by a NARSAD Independent Investigator’s Grant (21977) and grants from the National Institute of Mental Health (NIMH) to RM (R21MH103717 and R01MH113564). This research was supported, in part, by funding to RFT from the Canada Research Chairs program (Canada Research Chair in Pharmacogenomics), Canadian Institutes of Health Research (Foundation grant FDN-154294).

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RM designed the study. JJW performed the analyses supervised by RM. RM confirmed DSM-IV diagnostic status. JJW analyzed PET images, advised by PMR. JJW analyzed 1H-MRS, advised by SC. JJW drafted the manuscript with input from RM. EG managed structural MRI processing and quantification of hippocampal and intracranial volumes, advised by MC. RFT managed FAAH genotyping. RAR consulted on the endocannabinoid system. AAW designed and advised on [11C]CURB. RM, SH provided medical coverage for [11C]CURB PET scans. All authors provided critical feedback on the manuscript.

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Correspondence to Romina Mizrahi.

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RM is part of the SAB for a particular program at BI. RFT has consulted for Apotex and Quinn Emanuel, and Ethismos on unrelated topics. All other authors declare no competing interests.

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Watts, J.J., Guma, E., Chavez, S. et al. In vivo brain endocannabinoid metabolism is related to hippocampus glutamate and structure – a multimodal imaging study with PET, 1H-MRS, and MRI. Neuropsychopharmacol. 47, 1984–1991 (2022). https://doi.org/10.1038/s41386-022-01384-4

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