title: The Novel Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator, AZD8529, Decreases Nicotine Self-Administration and Relapse in Squirrel Monkeys.
abstract: BACKGROUND
  Based on rodent studies, group II metabotropic glutamate receptors (mGluR2 and mGluR3) were suggested as targets for addiction treatment. However, LY379268 and other group II agonists do not discriminate between the mainly presynaptic inhibitory mGluR2 (the proposed treatment target) and mGluR3. These agonists also produce tolerance over repeated administration and are no longer considered for addiction treatment. Here, we determined the effects of AZD8529, a selective positive allosteric modulator of mGluR2, on abuse-related effects of nicotine in squirrel monkeys and rats.
  
  
  METHODS
  We first assessed modulation of mGluR2 function by AZD8529 using functional in vitro assays in membranes prepared from a cell line expressing human mGluR2 and in primate brain slices. We then determined AZD8529 (.03-10 mg/kg, intramuscular injection) effects on intravenous nicotine self-administration and reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues. We also determined AZD8529 effects on food self-administration in monkeys and nicotine-induced dopamine release in accumbens shell in rats.
  
  
  RESULTS
  AZD8529 potentiated agonist-induced activation of mGluR2 in the membrane-binding assay and in primate cortex, hippocampus, and striatum. In monkeys, AZD8529 decreased nicotine self-administration at doses (.3-3 mg/kg) that did not affect food self-administration. AZD8529 also reduced nicotine priming- and cue-induced reinstatement of nicotine seeking after extinction of the drug-reinforced responding. In rats, AZD8529 decreased nicotine-induced accumbens dopamine release.
  
  
  CONCLUSIONS
  These results provide evidence for efficacy of positive allosteric modulators of mGluR2 in nonhuman primate models of nicotine reinforcement and relapse. This drug class should be considered for nicotine addiction treatment.
authors: Behavioral Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland. Electronic address: zjustino@intra.nida.nih.gov.
authors: Zuzana
authors: Z
authors: Justinova
authors: Behavioral Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland.
authors: Leigh V
authors: LV
authors: Panlilio
authors: Behavioral Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland.
authors: Maria E
authors: ME
authors: Secci
authors: Behavioral Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland.
authors: Godfrey H
authors: GH
authors: Redhi
authors: Behavioral Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland.
authors: Charles W
authors: CW
authors: Schindler
authors: AstraZeneca Neuroscience Innovative Medicines, Cambridge, Massachusetts.
authors: Alan J
authors: AJ
authors: Cross
authors: AstraZeneca Pharmaceuticals, Wilmington, Delaware.
authors: Ladislav
authors: L
authors: Mrzljak
authors: AstraZeneca Pharmaceuticals, Wilmington, Delaware.
authors: Amy
authors: A
authors: Medd
authors: Behavioral Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland.
authors: Yavin
authors: Y
authors: Shaham
authors: Behavioral Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland.
authors: Steven R
authors: SR
authors: Goldberg
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D018683:Excitatory Amino Acid Agents / Q000097:blood / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009538:Nicotine / Q000008:administration & dosage; D018722:Nicotinic Agonists / Q000008:administration & dosage; D010069:Oxadiazoles / Q000097:blood / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism; D012453:Saimiri; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: C000608263:AZD8529; D018683:Excitatory Amino Acid Agents; D007211:Indoles; D018722:Nicotinic Agonists; D010069:Oxadiazoles; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D009538:Nicotine; D004298:Dopamine
keywords: Allosteric modulation; Glutamate; Nicotine; Relapse; Self-administration; Smoking cessation