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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
Open accessAbstract
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.
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“The critical role of alternative reinforcers was elegantly brought into modern neuroscience by Ahmed et al., who showed that rats extensively trained to self-administer cocaine would readily forego the drug if offered a sweet solution as an alternative [103].This was later also found to be the case for heroin [103], methamphetamine [104] and alcohol [105].”
From Addiction as a brain disease revised: why it still matters, and the need for consilience (2021) · cites this paper as [104]
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Metadata
- Authors
- Caprioli, D., Venniro, M., Zeric, T., Li, X., Adhikary, S., Madangopal, R., Marchant, N. J., Lucantonio, F., Schoenbaum, G., Bossert, J. M., & Shaham, Y.
- Affiliations
- National Institutes of Health (US)
- Johns Hopkins University (US)
- Corresponding author
- Caprioli, Daniele
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 78
- Issue
- 7
- Pages
- 463-473
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4546920
- OpenAlex
- W2022691480
- Cited by
- 145
- References
- 88
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 6 · 2022: 14 · 2021: 16 · 2020: 19 · 2019: 6 · 2018: 20 · 2017: 21 · 2016: 20 · 2015: 5
- FWCI
- 10.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- AstraZeneca
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council (1053308)
- National Institute on Drug Abuse (ZIADA000434)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- incubation of craving, forced abstinence, mGluR2, positive allosteric modulators, relapse prevention, contingency management, extinction, self-administration
- MeSH terms
- Central Nervous System Stimulants, Animals, Cues, Disease Models, Animal, Extinction, Psychological, Food, Indoles, Methamphetamine, Oxadiazoles, Self Administration, Substance Withdrawal Syndrome, Time Factors, Volition, Receptors, Metabotropic Glutamate, Excitatory Amino Acid Agents, Amphetamine-Related Disorders, Rats, Drug-Seeking Behavior, Craving
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