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Published on: August 16, 2018
Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans
Kelly Smart1, Atsuko Nagano-Saito1, Michele S Milella1
1From 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).
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.
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