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

Smart, Kelly; Cox, Sylvia; Scala, Stephanie G.; Tippler, Maria; Jaworska, Natalia; Boivin, Michel; Séguin, Jean R.; Benkelfat, Chawki; Leyton, Marco

doi:10.1007/s00259-018-4252-4

Cited by 53 publications

(48 citation statements)

References 17 publications

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“…3D to G). As we observed previously in a larger sample, 38 the overall BP ND was higher in men than women (t 15 = −2.7, p = 0.015) by an average of 26% across re gions (Appendix 1, Figure S4). A single day 1 scan in each of the Amph and placebo groups was excluded because of low injected activity and high injected mass, respectively (Appen dix 1), resulting in a final sample size for primary PET com parisons of 9 Amphtreated participants and 8 placebo par ticipants.…”

Section: Availability Of Mglu5 In Humanssupporting

confidence: 79%

Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans

Smart

Nagano‐Saito

Milella

et al. 2021

jpn

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Background: Glutamate transmission is implicated in drug-induced behavioural sensitization and the associated long-lasting increases in mesolimbic output. Metabotropic glutamate type 5 (mGlu5) receptors might be particularly important, but most details are poorly understood. Methods: We first assessed in mice (n = 51, all male) the effects of repeated dextroamphetamine administration (2.0 mg/kg, i.p.) on locomotor activity and binding of the mGlu5 ligand [3H]ABP688. In a parallel study, in 19 stimulant-drug-naïve healthy human volunteers (14 female) we administered 3 doses of dextroamphetamine (0.3 mg/kg, p.o.) or placebo, followed by a fourth dose 2 weeks later. We measured [11C]ABP688 binding using positron emission tomography before and after the induction phase. We assessed psychomotor and behavioural sensitization using speech rate, eye blink rate and self-report. We measured the localization of mGlu5 relative to synaptic markers in mouse striatum using immunofluorescence. Results: We observed amphetamine-induced psychomotor sensitization in mice and humans. We did not see group differences in mGlu5 availability following 3 pre-challenge amphetamine doses, but group differences did develop in mice administered 5 doses. In mice and humans, individual differences in mGlu5 binding after repeated amphetamine administration were negatively correlated with the extent of behavioural sensitization. In drug-naïve mice, mGlu5 was expressed at 67% of excitatory synapses on dendrites of striatal medium spiny neurons. Limitations: Correlational results should be interpreted as suggestive because of the limited sample size. We did not assess sex differences. Conclusion: Together, these results suggest that changes in mGlu5 availability are not part of the earliest neural adaptations in stimulant-induced behavioural sensitization, but low mGlu5 binding might identify a higher propensity for sensitization.

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Section: Availability Of Mglu5 In Humanssupporting

confidence: 79%

Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans

Smart

Nagano‐Saito

Milella

et al. 2021

jpn

Self Cite

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“…Indeed, despite the presence of mGlu5 receptors in the cerebellum, only a negligible fraction specifically binds to the radiotracer [ 58 ], minimizing the likelihood of a bias or difference in cerebellar uptake between our groups. Instead, we recently documented that much of the variability in [ 11 C]ABP688 BP ND [ 59 ] reflects effects of time of day [ 60 ], (Z)- isomer content in the synthesized batch of tracer [ 53 ], and sex [ 54 ]. All three factors were controlled for in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…For all ANCOVAs and t -tests, sex, isomer ratio, AUDIT scores, tobacco smoking status and drug use (other than cannabis) were included as covariates. Each of these factors is associated with differences in [ 11 C]ABP688 BP ND [ 22 – 24 , 26 , 53 , 54 ]. Greenhouse-Geisser corrections were applied when the assumption of sphericity was violated ( p < 0.05).…”

Section: Methodsmentioning

confidence: 99%

mGlu5 receptor availability in youth at risk for addictions: effects of vulnerability traits and cannabis use

Cox

Tippler

Jaworska

et al. 2020

Neuropsychopharmacol.

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The excitatory neurotransmitter glutamate has been implicated in experience-dependent neuroplasticity and drug-seeking behaviors. Type 5 metabotropic glutamate (mGlu5) receptors might be particularly important. They are critically involved in synaptic plasticity and their availability has been reported to be lower in people with alcohol, tobacco, and cocaine use disorders. Since these reductions could reflect effects of drug use or pre-existing traits, we used positron emission tomography to measure mGlu5 receptor availability in young adults at elevated risk for addictions. Fifty-nine participants (age 18.5 ± 0.6) were recruited from a longitudinal study that has followed them since birth. Based on externalizing traits that predict future substance use problems, half were at low risk, half were at high risk. Cannabis use histories varied markedly and participants were divided into three subgroups: zero, low, and high use. Compared to low risk volunteers, those at elevated risk had lower [11C]ABP688 binding potential (BPND) values in the striatum, amygdala, insula, and orbitofrontal cortex (OFC). Cannabis use by risk group interactions were observed in the striatum and OFC. In these regions, low [11C]ABP688 BPND values were only seen in the high risk group that used high quantities of cannabis. When these high risk, high cannabis use individuals were compared to all other participants, [11C]ABP688 BPND values were lower in the striatum, OFC, and insula. Together, these results provide evidence that mGlu5 receptor availability is low in youth at elevated risk for addictions, particularly those who frequently use cannabis.

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“…Other studies from the same research group showed that the whole brain [ 11 C]ABP688 ( 82 ) BP ND was 17% higher in men than in women, irrespective of the menstrual phase or hormonal contraceptive use of the female subjects [ 178 ]. Another [ 11 C]ABP688 ( 82 ) study in 18 men and 13 women did not show any significant gender difference, and only a hint of a decline in BP ND as a function of age [ 179 ].…”

Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

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

Cited by 53 publications

References 17 publications

Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans

Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans

mGlu5 receptor availability in youth at risk for addictions: effects of vulnerability traits and cannabis use

A Review of Molecular Imaging of Glutamate Receptors

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