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

J Psychiatry Neurosci. 2021 Jan 4;46(1):E1-E13. doi: 10.1503/jpn.190162.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Behavior, Animal / drug effects
  • Central Nervous System Sensitization / drug effects*
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / pharmacology*
  • Corpus Striatum* / diagnostic imaging
  • Corpus Striatum* / drug effects
  • Corpus Striatum* / metabolism
  • Dextroamphetamine / administration & dosage
  • Dextroamphetamine / pharmacology*
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Locomotion / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Oximes / pharmacokinetics
  • Positron-Emission Tomography
  • Prefrontal Cortex* / diagnostic imaging
  • Prefrontal Cortex* / drug effects
  • Prefrontal Cortex* / metabolism
  • Psychomotor Performance / drug effects*
  • Pyridines / pharmacokinetics
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors
  • Receptor, Metabotropic Glutamate 5 / drug effects*
  • Receptor, Metabotropic Glutamate 5 / metabolism*


  • 3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime
  • Central Nervous System Stimulants
  • GRM5 protein, human
  • Grm5 protein, mouse
  • Oximes
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Dextroamphetamine