Effect of the Novel Positive Allosteric Modulator of Metabotropic Glutamate Receptor 2 AZD8529 on Incubation of Methamphetamine Craving After Prolonged Voluntary Abstinence in a Rat Model

Biol Psychiatry. 2015 Oct 1;78(7):463-73. doi: 10.1016/j.biopsych.2015.02.018. Epub 2015 Feb 23.


Background: Cue-induced methamphetamine craving increases after prolonged forced (experimenter-imposed) abstinence from the drug (incubation of methamphetamine craving). Here, we determined whether this incubation phenomenon would occur under conditions that promote voluntary (self-imposed) abstinence. We also determined the effect of the novel metabotropic glutamate receptor 2 positive allosteric modulator, AZD8529, on incubation of methamphetamine craving after forced or voluntary abstinence.

Methods: We trained rats to self-administer palatable food (6 sessions) and then to self-administer methamphetamine under two conditions: 12 sessions (9 hours/day) or 50 sessions (3 hours/day). We then assessed cue-induced methamphetamine seeking in extinction tests after 1 or 21 abstinence days. Between tests, the rats underwent either forced abstinence (no access to the food- or drug-paired levers) or voluntary abstinence (achieved via a discrete choice procedure between methamphetamine and palatable food; 20 trials per day) for 19 days. We also determined the effect of subcutaneous injections of AZD8529 (20 and 40 mg/kg) on cue-induced methamphetamine seeking 1 day or 21 days after forced or voluntary abstinence.

Results: Under both training and abstinence conditions, cue-induced methamphetamine seeking in the extinction tests was higher after 21 abstinence days than after 1 day (incubation of methamphetamine craving). AZD8529 decreased cue-induced methamphetamine seeking on day 21 but not day 1 of forced or voluntary abstinence.

Conclusions: We introduce a novel animal model to study incubation of drug craving and cue-induced drug seeking after prolonged voluntary abstinence, mimicking the human condition of relapse after successful contingency management treatment. Our data suggest that positive allosteric modulators of metabotropic glutamate receptor 2 should be considered for relapse prevention.

Keywords: Abstinence; Addiction models; Discrete choice; Extended access; Glutamate; Incubation of drug craving; Palatable food; Positive allosteric modulator; Psychostimulants; Relapse; Self-administration; mGluR2/3.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine-Related Disorders / drug therapy*
  • Amphetamine-Related Disorders / metabolism
  • Animals
  • Central Nervous System Stimulants / administration & dosage*
  • Craving / drug effects*
  • Craving / physiology
  • Cues
  • Disease Models, Animal
  • Drug-Seeking Behavior / drug effects
  • Drug-Seeking Behavior / physiology
  • Excitatory Amino Acid Agents / pharmacology*
  • Extinction, Psychological
  • Food
  • Indoles / pharmacology*
  • Methamphetamine / administration & dosage*
  • Oxadiazoles / pharmacology*
  • Rats
  • Receptors, Metabotropic Glutamate / metabolism
  • Self Administration
  • Substance Withdrawal Syndrome / drug therapy
  • Substance Withdrawal Syndrome / metabolism
  • Time Factors
  • Volition


  • AZD8529
  • Central Nervous System Stimulants
  • Excitatory Amino Acid Agents
  • Indoles
  • Oxadiazoles
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • Methamphetamine