Elsevier

Biological Psychiatry

Volume 78, Issue 7, 1 October 2015, Pages 463-473
Biological Psychiatry

Archival Report
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

https://doi.org/10.1016/j.biopsych.2015.02.018Get rights and content

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 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.

Section snippets

Methods and Materials

See supplement 1 for details on subjects, drugs, intravenous surgery, apparatus, procedures, abstinence phase, extinction tests, and statistical analyses.

Experiment 1: Incubation of Methamphetamine Craving After Short-Term Extended Daily Drug Access

The rats increased their food and methamphetamine intake over sessions (Figure 1A,B), and as in our previous study, extended access (9 hours/day) of methamphetamine led to strong escalation of drug intake (26, 53, 55). The repeated measures analysis of variance showed a significant effect of session for both food (F5,100 = 3.5, p < .01) and methamphetamine (F11,220 = 37.5, p < .001). During the three discrete choice sessions, the rats showed a strong preference for the food (p < .01, Figure 1C).

Discussion

There are two main findings in our study. First, time-dependent increases in cue-induced methamphetamine seeking (incubation of methamphetamine craving) were reliably observed after prolonged periods of choice-based voluntary abstinence. This effect was observed under two different self-administration procedures that are widely used to model drug addiction: extended daily access drug self-administration procedure (40, 41) and a long-term training procedure used to identify addicted rats based

Acknowledgments and Disclosures

This research was supported by the National Institute on Drug Abuse, Intramural Research Program funds (YS and GS). NJM received support from Early Career Fellowship 1053308 by the National Health and Medical Research Council.

DC, MV, TZ, XL, SA, RM, NJM, FL, and JMB carried out the experiments; DC, MV, and YS performed data analysis. DC, GS, FL, and YS designed the study and wrote the manuscript with MV. All authors critically reviewed the content and approved the final version before

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