title: Stress-induced reinstatement of alcohol-seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L822429.
abstract: BACKGROUND
  Genetic inactivation or pharmacological antagonism of neurokinin 1 (NK1) receptors blocks morphine and alcohol reward in rodents, while NK1 antagonism decreases alcohol craving in humans. The role of the NK1 system for relapse-like behavior has not previously been examined.
  
  
  OBJECTIVE
  Divergence between human and rodent NK1 receptors has limited the utility of NK1 antagonists developed for the human receptor species for preclinical studies of addiction-related behaviors in rats. Here we used L822429, an NK1 antagonist specifically engineered to bind at high affinity to the rat receptor, to assess the effects of NK1 receptor antagonism on alcohol-seeking behaviors in rats.
  
  
  METHODS
  L822429 (15 and 30 mg/kg) was used to examine effects of NK1 receptor antagonism on operant self-administration of 10% alcohol in 30-min daily sessions, as well as intermittent footshock stress- and cue-induced reinstatement of alcohol-seeking after extinction of lever responding.
  
  
  RESULTS
  At the doses used, L822429 did not significantly affect alcohol self-administration or cue-induced reinstatement, but potently and dose dependently suppressed stress-induced reinstatement of alcohol seeking, with an essentially complete suppression at the highest dose. The effect of L822429 on stress-induced reinstatement was behaviorally specific. The drug had no effect on conditioned suppression of operant responding following fear conditioning, locomotor activity, or self-administration of a sucrose solution.
  
  
  CONCLUSIONS
  To the degree that the reinstatement model provides a model of drug relapse, the results provide support for NK1 antagonism as a promising mechanism for pharmacotherapy of alcoholism, acting through suppression of stress-induced craving and relapse.
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Drive, Building 10-CRC, Room 1-5330, Bethesda, MD 20892-1108, USA.
authors.forename: Jesse R
authors.initials: JR
authors.lastname: Schank
authors.forename: Charles L
authors.initials: CL
authors.lastname: Pickens
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Rowe
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Annika
authors.initials: A
authors.lastname: Thorsell
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Yavin
authors.initials: Y
authors.lastname: Shaham
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy; D003216:Conditioning, Operant / Q000187:drug effects*; D003463:Cues; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D005239:Fear / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D055502:Secondary Prevention; D012646:Self Administration; D013045:Species Specificity; D013315:Stress, Psychological; D013395:Sucrose / Q000008:administration & dosage
chemical_list: C532739:N-((2-cyclopropoxy-5-(5-trifluomethyl)tetrazol-1-yl)benzyl)-2-phenylpiperidin-3-amine; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D000431:Ethanol; D013395:Sucrose