Sex differences in [ 11 C]ABP688 binding: a positron emission tomography study of mGlu5 receptors

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Abstract

Purpose

The purpose of this study was to assess, in a large sample of healthy young adults, sex differences in the binding potential of [ ¹¹C]ABP688, a positron emission tomography (PET) tracer selective for the metabotropic glutamate type 5 (mGlu5) receptor.

Methods

High resolution [ ¹¹C]ABP688 PET scans were acquired in 74 healthy volunteers (25 male, 49 female, mean age 20 ± 3.0). Mean binding potential (BP _ND = f _ND * (B _avail / K _D)) values were calculated in the prefrontal cortex, striatum, and limbic regions using the simplified reference tissue model with cerebellar grey matter as the reference region.

Results

[ ¹¹C]ABP688 BP _ND was significantly higher in men compared to women in the prefrontal cortex ( p < 0.01), striatum ( p < 0.001), and hippocampus ( p < 0.05). Whole-brain BP _ND was 17% higher in men. BP _ND was not related to menstrual phase in women.

Conclusions

Binding availability of mGlu5 receptors as measured by PET [ ¹¹C]ABP688 is higher in healthy men than women. This likely represents a source of variability in [ ¹¹C]ABP688 studies and could have relevance for sex differences in cognitive-behavioral functions and neuropsychiatric disorders.

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Most cited references 15

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Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression

Irina Esterlis, Nicole DellaGioia, Robert H Pietrzak … (2017)

The mechanisms of action of the rapid antidepressant effects of ketamine, an NMDA glutamate receptor antagonist, have not been fully elucidated. This study examined effects of ketamine on ligand binding to a metabotropic glutamatergic receptor (mGluR5) in individuals with major depressive disorder (MDD) and healthy controls. Thirteen healthy and thirteen MDD nonsmokers participated in two [11C]ABP688 positron emission tomography (PET) scans on the same day – before and during intravenous ketamine administration – and a third scan 1 day later. At baseline, significantly lower [11C]ABP688 binding was detected in the MDD as compared to the control group. We observed a significant ketamine-induced reduction in mGluR5 availability, (i.e. [11C]ABP688 binding), in both MDD and control subjects (average of 14±9% and 19±22%, respectively; p<0.01 for both), which persisted 24 hours later. There were no differences in ketamine-induced changes between MDD and control groups at either time point (p=0.8). A significant reduction in depressive symptoms was observed following ketamine administration in the MDD group (p<0.001), which was associated with the change in binding (p<0.04) immediately post ketamine. We hypothesize that glutamate released after ketamine administration moderates mGluR5 availability; this change appears to be related to antidepressant efficacy. The sustained decrease in binding may reflect prolonged mGluR5 internalization in response to the glutamate surge.

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Membrane estrogen receptors activate the metabotropic glutamate receptors mGluR5 and mGluR3 to bidirectionally regulate CREB phosphorylation in female rat striatal neurons.

D Grove, M B Boulware, P G Mermelstein (2010)

Along with its ability to directly regulate gene expression, estradiol influences cell signaling and brain functions via rapid, membrane-initiated events. In the female rat striatum, estradiol activates membrane-localized estrogen receptors to influence synaptic neurotransmission, calcium channel activity, and behaviors related to motor control. Yet, the mechanism by which estradiol acts to rapidly affect striatal physiology has remained elusive. Here we find that membrane estrogen receptors (ERs) couple to the metabotropic glutamate receptors mGluR5 and mGluR3, providing the framework to understand how membrane estrogen receptors affect striatal function. Using CREB phosphorylation as a downstream measure of ER/mGluR activation, membrane-localized estrogen receptor α (ERα) activates mGluR5 signaling to mediate mitogen-activated protein kinase (MAPK)-dependent CREB phosphorylation. Further, ERα and estrogen receptor β (ERβ) activate mGluR3 to attenuate L-type calcium channel-dependent CREB signaling. Interestingly, while this fundamental mechanism of ER/mGluR signaling was initially characterized in hippocampal neurons, estrogen receptors in striatal neurons are paired with a different set of mGluRs, resulting in the potential to functionally isolate membrane-initiated estrogen signaling across brain regions via use of specific mGluR modulators. These results provide both a mechanism for the rapid actions of estrogens within the female striatum, as well as demonstrate that estrogen receptors can interact with a more diverse set of surface membrane receptors than previously recognized. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

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Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [11C]ABP688 positron emission tomography.

Funda Akkus, Daniel S. Umbricht, Baltazar Gomez-Mancilla … (2013)

Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 receptor binding specifically to an allosteric site was observed by using positron emission tomography with [(11)C]ABP688. We found a marked global reduction (20.6%; P < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbitofrontal cortex. Compared with 14 nonsmokers, 14 ex-smokers had global reductions in the average gray matter mGluR5 DVR (11.5%; P < 0.005), and there was a significant difference in average gray matter mGluR5 DVR between smokers and ex-smokers (9.2%; P < 0.01). Clinical variables reflecting current nicotine consumption, dependence and abstinence were not correlated with mGluR5 DVR. This decrease in mGluR5 receptor binding may be an adaptation to chronic increases in glutamate induced by chronic nicotine administration, and the decreased down-regulation seen in the ex-smokers could be due to incomplete recovery of the receptors, especially because the ex-smokers were abstinent for only 25 wk on average. These results encourage the development and testing of drugs against addiction that directly target the glutamatergic system.

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Author and article information

Contributors

Marco Leyton: +1-514-3985804 , marco.leyton@mcgill.ca

Journal

Journal ID (nlm-ta): Eur J Nucl Med Mol Imaging

Journal ID (iso-abbrev): Eur. J. Nucl. Med. Mol. Imaging

Title: European Journal of Nuclear Medicine and Molecular Imaging

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 1619-7070

ISSN (Electronic): 1619-7089

Publication date (Electronic): 9 January 2019

Publication date PMC-release: 9 January 2019

Publication date (Print): 2019

Volume: 46

Issue: 5

Pages: 1179-1183

Affiliations

[1 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Department of Psychiatry, , McGill University, ; 1033 Pine Avenue West, Montreal, QC H3A 1A1 Canada

[2 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, Department of Cellular and Molecular Medicine, , University of Ottawa, ; Ottawa, ON K1H 8M5 Canada

[3 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, Institute of Mental Health Research, , affiliated with the University of Ottawa, ; Ottawa, ON K1Z 7K4 Canada

[4 ]ISNI 0000 0004 1936 8390, GRID grid.23856.3a, Department of Psychology, , Université Laval, ; Quebec City, QC G1V 0A6 Canada

[5 ]ISNI 0000 0001 2173 6322, GRID grid.411418.9, CHU Ste-Justine Research Center, ; Montreal, QC H3T 1C5 Canada

[6 ]ISNI 0000 0001 2292 3357, GRID grid.14848.31, Department of Psychiatry and Addiction, , Université de Montréal, ; Montreal, QC H3T 1J4 Canada

[7 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Department of Neurology & Neurosurgery, Montreal Neurological Institute, , McGill University, ; Montreal, QC H3A 2B4 Canada

[8 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Department of Psychology, , McGill University, ; Montreal, QC H3G 1G1 Canada

[9 ]ISNI 0000 0004 1936 8630, GRID grid.410319.e, Center for Studies in Behavioral Neurobiology, , Concordia University, ; Montreal, QC H4B 1R6 Canada

Article

Publisher ID: 4252

DOI: 10.1007/s00259-018-4252-4

PMC ID: 6451701

PubMed ID: 30627817

SO-VID: 8423f22d-657b-4fd9-97c9-387c7708a054

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 15 October 2018

Date accepted : 26 December 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;

Award ID: MOP119509

Award ID: MOP133537

Award Recipient : Chawki Benkelfat Marco Leyton

Funded by: FRQS ERA-NET

Custom metadata

ScienceOpen disciplines: Radiology & Imaging

Keywords: metabotropic glutamate receptors,mglur5,pet,gender

Data availability:

ScienceOpen disciplines: Radiology & Imaging

Keywords: metabotropic glutamate receptors, mglur5, pet, gender

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