The metabotropic glutamate 5 receptor modulates extinction and reinstatement of methamphetamine-seeking in mice

PLoS One. 2013 Jul 4;8(7):e68371. doi: 10.1371/journal.pone.0068371. Print 2013.


Methamphetamine (METH) is a highly addictive psychostimulant with no therapeutics registered to assist addicts in discontinuing use. Glutamatergic dysfunction has been implicated in the development and maintenance of addiction. We sought to assess the involvement of the metabotropic glutamate 5 receptor (mGlu5) in behaviours relevant to METH addiction because this receptor has been implicated in the actions of other drugs of abuse, including alcohol, cocaine and opiates. mGlu5 knockout (KO) mice were tested in intravenous self-administration, conditioned place preference and locomotor sensitization. Self-administration of sucrose was used to assess the response of KO mice to a natural reward. Acquisition and maintenance of self-administration, as well as the motivation to self-administer METH was intact in mGlu5 KO mice. Importantly, mGlu5 KO mice required more extinction sessions to extinguish the operant response for METH, and exhibited an enhanced propensity to reinstate operant responding following exposure to drug-associated cues. This phenotype was not present when KO mice were tested in an equivalent paradigm assessing operant responding for sucrose. Development of conditioned place preference and locomotor sensitization were intact in KO mice; however, conditioned hyperactivity to the context previously paired with drug was elevated in KO mice. These data demonstrate a role for mGlu5 in the extinction and reinstatement of METH-seeking, and suggests a role for mGlu5 in regulating contextual salience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine-Related Disorders / genetics
  • Amphetamine-Related Disorders / metabolism*
  • Amphetamine-Related Disorders / psychology
  • Animals
  • Behavior, Addictive / genetics
  • Behavior, Addictive / metabolism*
  • Behavior, Addictive / psychology
  • Central Nervous System Stimulants / administration & dosage*
  • Conditioning, Operant*
  • Cues
  • Extinction, Psychological*
  • Feeding Behavior
  • Gene Expression
  • Humans
  • Male
  • Methamphetamine / administration & dosage*
  • Mice
  • Mice, Knockout
  • Motivation
  • Receptor, Metabotropic Glutamate 5 / deficiency
  • Receptor, Metabotropic Glutamate 5 / genetics*
  • Reinforcement Schedule
  • Reward
  • Self Administration


  • Central Nervous System Stimulants
  • Grm5 protein, mouse
  • Receptor, Metabotropic Glutamate 5
  • Methamphetamine

Grant support

The present study was supported by a project grant (APP1022201) from the National Health and Medical Research Council (NHMRC) of Australia awarded to AL and JK, NHMRC fellowships and scholarships awarded to AL, RB, and RC, Australian Research Council Fellowship awarded to JK. RC also acknowledges support from Rotary Health Australia, as well as The Alan and Elizabeth Finkel Foundation. The authors acknowledge the Victorian Government’s Operational Infrastructure Support Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.