Kelly Smart, PhD; Atsuko Nagano-Saito, MD, PhD; Michele S. Milella, MD; Diana Yae Sakae, PhD; Mathieu Favier, PhD; Erika Vigneault, BSc; Leanne Louie, BSc; Alison Hamilton, PhD; Stephen S.G. Ferguson, PhD; Pedro Rosa-Neto, MD, PhD; Sridar Narayanan, PhD; Salah El Mestikawy, PhD*; Marco Leyton, PhD*; Chawki Benkelfat, MD, DERBH*
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.
*These authors contributed equally to this work.
Submitted Sep. 23, 2019; Revised Dec. 21, 2019; Accepted Feb. 3, 2020; Published online June 19, 2020
Acknowledgments: The authors thank Kevin Larcher for assistance with PET imaging and analysis, Arturo Aliaga for assistance with the rodent experiments and Dr. Nicolas Heck for technical assistance on the immunofluorescence experiments and distance analyses. This study used the services of the Molecular and Cellular Microscopy Platform in the Douglas Institute and the Cell Biology and Image Acquisition Core at the University of Ottawa.
Affiliations: From the Department of Psychiatry, McGill University, Montreal, Que. (Smart, Nagano-Saito, Milella, Sakae, Favier, Vigneault, Louie, Rosa-Neto, El Mestikawy, Leyton, Benkelfat); the Douglas Mental Health University Institute, McGill University, Montreal, Que. (Smart, Sakae, Favier, Vigneault, Rosa-Neto, El Mestikawy); the Department of Cellular and Molecular Medicine, University of Ottawa, Ont. (Hamilton, Ferguson); the McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Que. (Rosa-Neto, Narayanan, Leyton, Benkelfat); the Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Que. (Rosa-Neto, Narayanan, Leyton, Benkelfat); and the Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, Que. (Leyton).
Dr. Chawki Benkelfat passed away on Jan. 7, 2020, during preparation of this manuscript for publication.
Funding: This research was supported by funds from the Canadian Institutes for Health Research (C. Benkelfat and M. Leyton, MOP-119509), Brain Canada Multi-Investigator Research Initiative (S. El Mestikawy), Fond de Recherche Santé du Québec (S. El Mestikawy, FRQS 30582), Natural Sciences and Engineering Research Council (NSERC, RGPIN/386431-2012) Discovery (DG) Grants (S. El Mestikawy), ERANET-Neuron Joint Transnational Call for “European Research Projects on Mental Disorders” and research projects on synaptic dysfunction in disorders of the central nervous system JTC 2013 and 2017 (S. El Mestikawy). The sponsors had no role in the design or conduct of the study, in data collection, analysis or interpretation, in manuscript preparation, approval or review, or in the decision to submit the manuscript for publication.
Competing interests: M. Leyton is an associate editor of JPN. He was not involved in reviewing or the decision to accept this paper for publication.
Contributors: K. Smart, M. Milella, M. Favier, E. Vigneault, S. El Mestikawy, M. Leyton and C. Benkelfat designed the study. K. Smart, D. Yae Sakae, M. Favier, L. Louie, A. Hamilton, S. Ferguson and M. Leyton acquired the data, which K. Smart, A. Nagano-Saito, M. Favier, E. Vigneault, L. Louie, P. Rosa-Neto, S. Narayanan, S. El Mestikawy, M. Leyton and C. Benkelfat analyzed. K. Smart, S. El Mestikawy, M. Leyton and C. Benkelfat wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
Correspondence to: M. Leyton, Department of Psychiatry, McGill University, 1033 Pine Avenue W., Montreal QC Canada H3A 1A1; firstname.lastname@example.org; S. El Mestikawy, Douglas Mental Health Research Institute, 6875 Boulevard LaSalle, Montreal QC Canada, H4H 1R3; email@example.com