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

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 mGluR2 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 mGluR2 should be considered for relapse prevention.

Incubation of Methamphetamine but not Heroin Craving After Voluntary Abstinence in Male and Female Rats

“…We found that under both training conditions, methamphetamine seeking in the extinction tests was higher after 21 abstinence days than after 1 day, demonstrating incubation of drug craving after voluntary abstinence. We also found that 'incubated' drug seeking on voluntary abstinence day 21 was similar in magnitude to the incubated drug seeking observed on forced abstinence day 21 (Caprioli et al, 2015a).…”

“…Between tests, the rats underwent voluntary abstinence for 19 days (achieved via a mutually exclusive discrete choice procedure between methamphetamine and the palatable food in which, on any given trial, the rats can earn the food or drug reward but not both; 20 trials/day). Under our voluntary abstinence procedure, most rats achieve complete methamphetamine abstinence during most of the choice sessions (ie, zero choices of methamphetamine infusions), whereas some rats continue to occasionally self-administer a small number of drug infusions during these sessions (Caprioli et al, 2015a;Caprioli et al, 2016;Caprioli et al, 2015b) (see Figure 2). We found that under both training conditions, methamphetamine seeking in the extinction tests was higher after 21 abstinence days than after 1 day, demonstrating incubation of drug craving after voluntary abstinence.…”

“…Our model is based on studies showing that most rats strongly prefer the non-drug reward when given a mutually exclusive choice between cocaine or methamphetamine and palatable food (Cantin et al, 2010;Caprioli et al, 2015b;Lenoir et al, 2007). In our first study (Caprioli et al, 2015a), we trained food-sated male SpragueDawley rats to self-administer palatable food (6 sessions) and then to self-administer methamphetamine under two conditions: 12 sessions (9 h/day) or 50 sessions (3 h/day); we chose these training conditions based on the escalation or DSM-IV rodent addiction models (Ahmed and Koob, 1998;DerocheGamonet et al, 2004). We then assessed methamphetamine seeking in relapse tests after 1 or 21 abstinence days; during testing, lever presses led to contingent delivery of a light cue previously paired with methamphetamine infusions but not methamphetamine (extinction conditions).…”

“…Based on the above-mentioned 'translational' considerations, we recently developed a rat model of incubation of methamphetamine craving after prolonged alternative reward choice-based voluntary abstinence (Caprioli et al, 2015a;Caprioli et al, 2016). Our model is based on studies showing that most rats strongly prefer the non-drug reward when given a mutually exclusive choice between cocaine or methamphetamine and palatable food (Cantin et al, 2010;Caprioli et al, 2015b;Lenoir et al, 2007).…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Systemic administration of this compound decreases cued nicotine intake and cue-and nicotineinduced seeking (Justinova et al, 2015) as well as cueinduced methamphetamine seeking (Caprioli et al, 2015). Interestingly, AZD8529 was effective at inhibiting cued nicotine seeking at doses that did not affect food seeking, indicating that the selective activation of mGluR2 may prove a more effective treatment of relapse given the lack of a negative effect on natural rewards.…”