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

TitleMetabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans.
Publication TypeJournal Article
Year of Publication2020
AuthorsSmart K, Nagano-Saito A, Milella MS, Sakae DYae, Favier M, Vigneault E, Louie L, Hamilton A, Ferguson SSG, Rosa-Neto P, Narayanan S, Mestikawy SEl, Leyton M, Benkelfat C
JournalJ Psychiatry Neurosci
Volume45
Issue4
Pagination190162
Date Published2020 Jun 19
ISSN1488-2434
Abstract

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 neur.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.

DOI10.1503/jpn.190162
Alternate JournalJ Psychiatry Neurosci
PubMed ID32559027