title: Hypocretin/orexin signaling in the hypothalamic paraventricular nucleus is essential for the expression of nicotine withdrawal.
abstract: BACKGROUND
  Hypocretin (orexin) signaling is involved in drug addiction. In this study, we investigated the role of these hypothalamic neuropeptides in nicotine withdrawal by using behavioral and neuroanatomical approaches.
  
  
  METHODS
  Nicotine withdrawal syndrome was precipitated by mecamylamine (2 mg/kg, subcutaneous) in C57BL/6J nicotine-dependent mice (25 mg/kg/day for 14 days) pretreated with the hypocretin receptor 1 (Hcrtr-1) antagonist SB334867 (5 and 10 mg/kg, intraperitoneal), the hypocretin receptor 2 antagonist TCSOX229 (5 and 10 mg/kg, intraperitoneal), and in preprohypocretin knockout mice. c-Fos expression was analyzed in several brain areas related to nicotine dependence by immunofluorescence techniques. Retrograde tracing with rhodamine-labeled fluorescent latex microspheres was used to determine whether the hypocretin neurons project directly to the paraventricular nucleus of the hypothalamus (PVN), and SB334867 was locally administered intra-PVN (10 nmol/side) to test the specific involvement of Hcrtr-1 in this brain area during nicotine withdrawal.
  
  
  RESULTS
  Somatic signs of nicotine withdrawal were attenuated in mice pretreated with SB334867 and in preprohypocretin knockout mice. No changes were found in TCSOX229 pretreated animals. Nicotine withdrawal increased the percentage of hypocretin cells expressing c-Fos in the perifornical, dorsomedial, and lateral hypothalamus. In addition, the increased c-Fos expression in the PVN during withdrawal was dependent on hypocretin transmission through Hcrtr-1 activation. Hypocretin neurons directly innervate the PVN and the local infusion of SB334867 into the PVN decreased the expression of nicotine withdrawal.
  
  
  CONCLUSIONS
  These data demonstrate that hypocretin signaling acting on Hcrtr-1 in the PVN plays a crucial role in the expression of nicotine withdrawal.
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Plaza-Zabala
authors.forename: África
authors.initials: Á
authors.lastname: Flores
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Fernando
authors.initials: F
authors.lastname: Berrendero
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D001583:Benzoxazoles / Q000008:administration & dosage / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D057054:Molecular Imaging / Q000379:methods; D009287:Naphthyridines; D056347:Neuroanatomical Tract-Tracing Techniques / Q000379:methods; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D064446:Orexin Receptors; D000068797:Orexins; D010286:Paraventricular Hypothalamic Nucleus / Q000033:anatomy & histology / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D014029:Tobacco Use Disorder / Q000503:physiopathology*; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; C572065:1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone; D000954:Antigens, Surface; D001583:Benzoxazoles; C501103:Cd200r1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D009287:Naphthyridines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D008464:Mecamylamine; D014508:Urea