title: Differential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on nicotine versus cocaine self-administration and relapse in squirrel monkeys.
abstract: Group II metabotropic glutamate receptors (mGluR2 and mGluR3) have been suggested to play an important role in mediation of drug-reinforced behaviors, as well as in the mechanisms underlying relapse in abstinent subjects. The prototypical mGluR2/3 agonist, LY379268, has been shown to attenuate nicotine reinforcement and cue-induced reinstatement of drug seeking in rats, as well as reinstatement induced by drug-associated stimuli and contexts across different drugs of abuse (i.e., cocaine, heroin, and methamphetamine). However, in primates, LY379268 has been shown to produce conflicting results on abuse-related effects of cocaine, and there are no data available for nicotine.
  
  
  
  To explore the therapeutic potential of mGluR2/3 agonists, we compared the effects of LY379268 (0.03-1.0 mg/kg) on nicotine, cocaine, and food self-administration under a fixed-ratio (FR10) schedule in three separate groups of squirrel monkeys. Moreover, we studied the effects of LY379268 on nicotine/cocaine priming-induced and cue-induced reinstatement of drug-seeking behavior in nicotine- and cocaine-experienced groups of animals.
  
  
  
  LY379268 blocked nicotine, but not cocaine, self-administration in monkeys. There was a partial overlap between doses that affected nicotine and food self-administration. In abstinent monkeys, LY379268 dose-dependently blocked nicotine, but not cocaine, priming-induced reinstatement of drug seeking. In both cocaine-experienced and nicotine-experienced groups of animals, LY379268 potently reduced cue-induced reinstatement of drug-seeking behavior.
  
  
  
  The present findings provide strong support for the potential utility of mGlu2/3 receptor agonists for the treatment of nicotine dependence and suggest their utility for prevention of relapse induced by environmental cues associated with drug taking.
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA. zjustino@intra.nida.nih.gov.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
authors.affiliation: Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.|Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada.|Department of Pharmacology, University of Toronto, Toronto, ON, Canada.|Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Le Foll
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.
authors.forename: Godfrey H
authors.initials: GH
authors.lastname: Redhi
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D003463:Cues; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D008297:Male; D009538:Nicotine / Q000008:administration & dosage*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D012008:Recurrence; D012054:Reinforcement, Psychology; D012453:Saimiri; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000188:drug therapy*
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D009538:Nicotine; D003042:Cocaine
keywords: Cocaine; Glutamate; Nicotine; Reinstatement; Relapse; Self-administration; Smoking cessation; Squirrel monkey