1. Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans.
- Author
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Smart K, Nagano-Saito A, Milella MS, Sakae DY, Favier M, Vigneault E, Louie L, Hamilton A, Ferguson SSG, Rosa-Neto P, Narayanan S, El Mestikawy S, Leyton M, and Benkelfat C
- Subjects
- Adult, Animals, Behavior, Animal drug effects, Central Nervous System Stimulants administration & dosage, Dextroamphetamine administration & dosage, Female, Fluorescent Antibody Technique, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Oximes pharmacokinetics, Positron-Emission Tomography, Pyridines pharmacokinetics, Receptor, Metabotropic Glutamate 5 antagonists & inhibitors, Central Nervous System Sensitization drug effects, Central Nervous System Stimulants pharmacology, Corpus Striatum diagnostic imaging, Corpus Striatum drug effects, Corpus Striatum metabolism, Dextroamphetamine pharmacology, Locomotion drug effects, Prefrontal Cortex diagnostic imaging, Prefrontal Cortex drug effects, Prefrontal Cortex metabolism, Psychomotor Performance drug effects, Receptor, Metabotropic Glutamate 5 drug effects, Receptor, Metabotropic Glutamate 5 metabolism
- 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., 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., (© 2021 Joule Inc. or its licensors.)
- Published
- 2021
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