Effect of the novel positive allosteric modulator of mGluR ₂ AZD8529 on incubation of methamphetamine craving after prolonged voluntary abstinence in a rat model

Abstract

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 mGluR 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-hr/day) or 50 sessions (3-hr/day). We then assessed cue-induced methamphetamine seeking in extinctions test 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 for 19 days (achieved via a discrete choice procedure between methamphetamine and palatable food; 20 trials per day). We also determined the effect of subcutaneous injections of AZD8529 (20 and 40 mg/kg) on cue-induced methamphetamine seeking 1 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 PAMs of mGluR ₂ should be considered for relapse prevention.