Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement

Psychopharmacology (Berl). 2011 May;215(1):191-203. doi: 10.1007/s00213-010-2127-x. Epub 2010 Dec 22.


Rationale: 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.

MeSH terms

  • Alcoholism / metabolism
  • Alcoholism / prevention & control
  • Alcoholism / psychology
  • Animals
  • Behavior, Addictive / prevention & control*
  • Behavior, Addictive / psychology
  • Behavior, Animal / drug effects*
  • Conditioning, Operant / drug effects*
  • Dioxanes / administration & dosage
  • Dioxanes / pharmacology
  • Dioxanes / therapeutic use*
  • Disease Models, Animal
  • Ethanol / administration & dosage*
  • Male
  • Mice
  • Mice, Inbred DBA
  • Motor Activity / drug effects
  • Orexin Receptors
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / pharmacology
  • Phenylurea Compounds / therapeutic use*
  • Rats
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Reinforcement Schedule
  • Reinforcement, Psychology
  • Self Administration


  • Dioxanes
  • JNJ 10397049
  • Orexin Receptors
  • Phenylurea Compounds
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Ethanol