title: A role for hypocretin/orexin receptor-1 in cue-induced reinstatement of nicotine-seeking behavior.
abstract: Hypocretin/orexin signaling is critically involved in relapse to drug-seeking behaviors. In this study, we investigated the involvement of the hypocretin system in the reinstatement of nicotine-seeking behavior induced by nicotine-associated cues. Pretreatment with the hypocretin receptor-1 antagonist SB334867, but not with the hypocretin receptor-2 antagonist TCSOX229, attenuated cue-induced reinstatement of nicotine-seeking, which was associated with an activation of hypocretin neurons of the lateral and perifornical hypothalamic areas. In addition, relapse to nicotine-seeking increased the phosphorylation levels of GluR2-Ser880, NR1-Ser890, and p38 MAPK in the nucleus accumbens (NAc), but not in the prefrontal cortex. Notably, phosphorylation levels of NR1-Ser890 and p38 MAPK, but not GluR2-Ser880, were dependent on hypocretin receptor-1 activation. The intra-accumbens infusion of the protein kinase C (PKC) inhibitor NPC-15437 reduced nicotine-seeking behavior elicited by drug-paired cues consistent with the PKC-dependent phosphorylations of GluR2-Ser880 and NR1-Ser890. SB334867 failed to modify cue-induced reinstatement of food-seeking, which did not produce any biochemical changes in the NAc. These data identify hypocretin receptor-1 and PKC signaling as potential targets for the treatment of relapse to nicotine-seeking induced by nicotine-associated cues.
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat 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: Elena
authors.initials: E
authors.lastname: Martín-García
authors.forename: Rocío
authors.initials: R
authors.lastname: Saravia
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Fernando
authors.initials: F
authors.lastname: Berrendero
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D003463:Cues; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008845:Microinjections; D009287:Naphthyridines; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000378:metabolism; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000502:physiology*; D010766:Phosphorylation; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
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; D001583:Benzoxazoles; C121673:Gprin1 protein, mouse; C497459:Hcrtr1 protein, mouse; C578628:Hcrtr2 protein, mouse; D007546:Isoquinolines; D009287:Naphthyridines; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C069701:NPC 15437; D009538:Nicotine; D014508:Urea; D048051:p38 Mitogen-Activated Protein Kinases; C104722:glutamate receptor ionotropic, AMPA 2