title: Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement.
abstract: BACKGROUND
  Orexin-1 receptor antagonists have been shown to block the reinforcing effects of drugs of abuse and food. However, whether blockade of orexin-2 receptor has similar effects has not been determined. We have recently described the in vitro and in vivo effects of JNJ-10397049, a selective and brain penetrant orexin-2 receptor antagonist.
  
  
  OBJECTIVE
  The goal of these studies was to evaluate whether systemic administration of JNJ-10397049 blocks the rewarding effects of ethanol and reverses ethanol withdrawal in rodents. As a comparison, SB-408124, a selective orexin-1 receptor antagonist, was also evaluated.
  
  
  METHODS
  Rats were trained to orally self-administer ethanol (8% v/v) or saccharin (0.1% v/v) under a fixed-ratio 3 schedule of reinforcement. A separate group of rats received a liquid diet of ethanol (8% v/v) and withdrawal signs were evaluated 4 h after ethanol discontinuation. In addition, ethanol-induced increases in extracellular dopamine levels in the nucleus accumbens were tested. In separate experiments, the acquisition, expression, and reinstatement of conditioned place preference (CPP) were evaluated in mice.
  
  
  RESULTS
  Our results indicate that JNJ-10397049 (1, 3, and 10 mg/kg, sc) dose-dependently reduced ethanol self-administration without changing saccharin self-administration, dopamine levels, or withdrawal signs in rats. Treatment with JNJ-10397049 (10 mg/kg, sc) attenuated the acquisition, expression, and reinstatement of ethanol CPP and ethanol-induced hyperactivity in mice. Surprisingly, SB-408124 (3, 10 and 30 mg/kg, sc) did not have any effect in these procedures.
  
  
  CONCLUSIONS
  Collectively, these results indicate, for the first time, that blockade of orexin-2 receptors is effective in reducing the reinforcing effects of ethanol.
authors.affiliation: Neuroscience, Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, CA 92121, USA. jshobloc@its.jnj.com
authors.forename: James R
authors.initials: JR
authors.lastname: Shoblock
authors.forename: Natalie
authors.initials: N
authors.lastname: Welty
authors.forename: Leah
authors.initials: L
authors.lastname: Aluisio
authors.forename: Ian
authors.initials: I
authors.lastname: Fraser
authors.forename: S Timothy
authors.initials: ST
authors.lastname: Motley
authors.forename: Kirsten
authors.initials: K
authors.lastname: Morton
authors.forename: James
authors.initials: J
authors.lastname: Palmer
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
authors.forename: Jamin
authors.initials: J
authors.lastname: Boggs
authors.forename: Ruggero
authors.initials: R
authors.lastname: Galici
mesh_terms: D000437:Alcoholism / Q000378:metabolism / Q000517:prevention & control / Q000523:psychology; D000818:Animals; D016739:Behavior, Addictive / Q000517:prevention & control* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects*; D004146:Dioxanes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D064446:Orexin Receptors; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D004146:Dioxanes; C524573:JNJ 10397049; D064446:Orexin Receptors; D010671:Phenylurea Compounds; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D000431:Ethanol