title: The role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking in rats.
abstract: BACKGROUND
  Stress is related to heavy alcohol use and relapse in alcoholics. Using the reinstatement model, we have shown that corticotropin-releasing factor (CRF) underlies stress-induced relapse to alcohol seeking in laboratory rodents. Little is known about how other neurotransmitters interact with CRF in these effects. Dynorphin and its receptor (kappa opioid receptor, KOR) are involved in stress responses and in alcohol seeking. KOR and CRF receptors (CRF R) may interact in the production of stress-related behaviors but it is not known whether this interaction is involved in reinstatement of alcohol seeking.
  
  
  METHODS
  Male Long Evans rats were trained to self-administer alcohol (12% w/v). After extinction of responding, we determined the effects of the KOR agonist, U50,488 (2.5, 5 mg/kg) on reinstatement of alcohol seeking, and their sensitivity to the selective KOR antagonist nor-binaltorphimine dihydrochloride (nor-BNI) (10 mg/kg) administered at different times before U50,488. We then examined the effects of nor-BNI on reinstatement induced by the stressor yohimbine (1.25 mg/kg) and on reinstatement induced by exposure to alcohol-associated cues. Finally, we determined whether CRF R1 blockade with antalarmin (10, 20 mg/kg) attenuates alcohol seeking induced by U50,488.
  
  
  RESULTS
  U50,488 reinstated alcohol seeking. Prior treatment with nor-BNI 2, but not 24 h before administration of U50,488 or yohimbine blocked reinstatement induced by these drugs. Cue-induced reinstatement was blocked by nor-BNI administered 2 h prior to testing. Finally, U50,488-induced reinstatement was blocked by antalarmin.
  
  
  CONCLUSIONS
  These data further support a role for KOR in reinstatement of alcohol seeking under nonstress and stressful conditions and that KOR and CRF R interact in these effects.
authors.affiliation: Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health Toronto, Canada.
authors.forename: Douglas
authors.initials: D
authors.lastname: Funk
authors.affiliation: Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health Toronto, Canada.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Coen
authors.affiliation: Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health Toronto, Canada ; Department of Pharmacology, University of Toronto Toronto, Canada ; Department of Psychiatry, University of Toronto Toronto, 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; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D016739:Behavior, Addictive; D001522:Behavior, Animal / Q000187:drug effects; D003463:Cues; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012646:Self Administration; D013312:Stress, Physiological / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D017473:Receptors, Opioid, kappa; C103016:antalarmin; D015016:Yohimbine; C051844:norbinaltorphimine; D000431:Ethanol; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
keywords: Alcohol self-administration; CRF receptors; conditioned cue; kappa opioid receptors; reinstatement; stress