title: Role of the kappa-opioid receptor system in stress-induced reinstatement of nicotine seeking in rats.
abstract: BACKGROUND
  The correlation between stress and smoking is well established. The mechanisms that underlie this relationship are, however, unclear. Recent data suggest that the kappa-opioid system is involved in the mediation of negative affective states associated with stress thereby promoting drug addiction and relapse. Pharmacological treatments targeting the kappa-opioid system and this mechanism may prove to be useful therapeutics for nicotine addiction in the future.
  
  
  OBJECTIVE
  We sought to determine whether there was a stress-specific role of the kappa-opioid system in nicotine seeking behavior.
  
  
  METHODS
  Groups of male Long Evans rats were trained to self-administer nicotine intravenously; their operant responding for nicotine was extinguished prior to tests of reinstatement. Pretreatment with systemic injections of the kappa-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was given prior to tests of stress (systemic injections of yohimbine (YOH)) or cue-induced reinstatement of nicotine seeking. Systemic injections of the KOR agonist U50,488 were also given in a test for reinstatement of nicotine seeking.
  
  
  RESULTS
  Nor-BNI pretreatment at 1h and 24h prior to testing was able to block YOH-induced, but not cue-induced reinstatement of nicotine seeking. U50,488 reinstated nicotine seeking behavior in a dose-dependent manner.
  
  
  CONCLUSIONS
  These findings support the hypothesis that the kappa-opioid system is involved in relapse to nicotine seeking induced by stress, but not by conditioned cues. KOR antagonists such as nor-BNI may therefore be useful novel therapeutic agents for decreasing the risk of stress-induced drug relapse.
authors.affiliation: Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, 33 Russell St., Toronto, Ontario M5S 2S1, Canada; Department of Pharmacology & Toxicology, University of Toronto, Medical Sciences Building, Rm 4207, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Grella
authors.affiliation: Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, 33 Russell St., Toronto, Ontario M5S 2S1, Canada. Electronic address: douglas.funk@camh.ca.
authors.forename: Douglas
authors.initials: D
authors.lastname: Funk
authors.affiliation: Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, 33 Russell St., Toronto, Ontario M5S 2S1, Canada.
authors.forename: Kathy
authors.initials: K
authors.lastname: Coen
authors.affiliation: Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, 33 Russell St., Toronto, Ontario M5S 2S1, Canada.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Li
authors.affiliation: Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, 33 Russell St., Toronto, Ontario M5S 2S1, Canada; Department of Pharmacology & Toxicology, University of Toronto, Medical Sciences Building, Rm 4207, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Department of Psychiatry, University of Toronto, 250 College Street, 8th Floor, Toronto, Ontario M5T 1R8, Canada.
authors.forename: A D
authors.initials: AD
authors.lastname: Lê
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D051381:Rats; D020318:Rats, Long-Evans; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D012646:Self Administration; D013315:Stress, Psychological / Q000209:etiology* / Q000517:prevention & control*; D014029:Tobacco Use Disorder / Q000150:complications*; D015016:Yohimbine / Q000633:toxicity
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D018712:Analgesics, Non-Narcotic; D018722:Nicotinic Agonists; D017473:Receptors, Opioid, kappa; D015016:Yohimbine; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009538:Nicotine
keywords: Nicotine; Nor-binaltorphimine; Reinstatement; Stress; U50,488; Yohimbine