title: 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 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.
authors: Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland. Electronic address: daniele.caprioli@nih.gov.
authors: Daniele
authors: D
authors: Caprioli
authors: Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland; Neuropsychopharmacology Laboratory, Section of Pharmacology, Department Public Health and Community Medicine, University of Verona, Verona, Italy.
authors: Marco
authors: M
authors: Venniro
authors: Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland.
authors: Tamara
authors: T
authors: Zeric
authors: Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland.
authors: Xuan
authors: X
authors: Li
authors: Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland.
authors: Sweta
authors: S
authors: Adhikary
authors: Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland.
authors: Rajtarun
authors: R
authors: Madangopal
authors: Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland; Florey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors: Nathan J
authors: NJ
authors: Marchant
authors: The Solomon H. Snyder Department of Neuroscience, Brain Science Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Federica
authors: F
authors: Lucantonio
authors: Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland.
authors: Geoffrey
authors: G
authors: Schoenbaum
authors: Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland.
authors: Jennifer M
authors: JM
authors: Bossert
authors: Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland.
authors: Yavin
authors: Y
authors: Shaham
mesh_terms: D019969:Amphetamine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D066249:Craving / Q000187:drug effects* / Q000502:physiology; D003463:Cues; D004195:Disease Models, Animal; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D005108:Extinction, Psychological; D005502:Food; D007211:Indoles / Q000494:pharmacology*; D008694:Methamphetamine / Q000008:administration & dosage*; D010069:Oxadiazoles / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors; D014836:Volition
chemical_list: C000608263:AZD8529; D000697:Central Nervous System Stimulants; D018683:Excitatory Amino Acid Agents; D007211:Indoles; D010069:Oxadiazoles; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D008694:Methamphetamine
keywords: Abstinence; Addiction models; Discrete choice; Extended access; Glutamate; Incubation of drug craving; Palatable food; Positive allosteric modulator; Psychostimulants; Relapse; Self-administration; mGluR2/3