title: The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid reward.
abstract: BACKGROUND
  Cannabis is the most widely used illicit drug in the world. Although there is a high prevalence of users who seek treatment for cannabis dependence, no accepted pharmacologic treatment is available to facilitate and maintain abstinence. The hypocretin/orexin system plays a critical role in drug addiction, but the potential participation of this system in the addictive properties of cannabinoids is unknown.
  
  
  METHODS
  We investigated the effects of hypocretins in the intravenous self-administration of the synthetic cannabinoid agonist WIN55,212-2 using hypocretin receptor-1 (Hcrtr-1) and hypocretin receptor-2 antagonists and Hcrtr-1 knockout mice. Additional groups of mice were trained to obtain water to rule out operant responding impairments. Activation of hypocretin neurons was analyzed by using double-label immunofluorescence of FosB/ΔFosB with hypocretin-1. Microdialysis studies were performed to evaluate dopamine extracellular levels in the nucleus accumbens after acute Δ(9)-tetrahydrocannabinol administration.
  
  
  RESULTS
  Systemic administration of the Hcrtr-1 antagonist SB334867 reduced intravenous self-administration of WIN55,212-2, as well as the maximum effort to obtain a WIN55,212-2 infusion, as revealed under a progressive ratio schedule. This role of Hcrtr-1 in the reinforcing and motivational properties of WIN55,212-2 was confirmed in Hcrtr-1 knockout mice. Contingent, but not noncontingent, WIN55,212-2 self-administration increased the percentage of hypocretin cells expressing FosB/ΔFosB in the lateral hypothalamus. The enhancement in dopamine extracellular levels in the nucleus accumbens induced by Δ(9)-tetrahydrocannabinol was blocked in mice lacking the Hcrtr-1.
  
  
  CONCLUSIONS
  These findings demonstrate that Hcrtr-1 modulates the reinforcing properties of cannabinoids, which could have a clear therapeutic interest.
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: África
authors.initials: Á
authors.lastname: Flores
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: fernando.berrendero@upf.edu.
authors.forename: Fernando
authors.initials: F
authors.lastname: Berrendero
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D013759:Dronabinol / Q000494:pharmacology*; D007026:Hypothalamic Area, Lateral / Q000378:metabolism; D008297:Male; D002189:Marijuana Abuse / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D009287:Naphthyridines; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D048588:Benzoxazines; D001583:Benzoxazoles; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; C497459:Hcrtr1 protein, mouse; D009025:Morpholines; D009281:Naphthalenes; D009287:Naphthyridines; C497461:OX2 protein, mouse; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D016760:Proto-Oncogene Proteins c-fos; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D014508:Urea; D004298:Dopamine
keywords: 212-2; Cannabinoid; WIN55; dopamine; hypocretin; knockout; reward