title: The hypocretin/orexin system mediates the extinction of fear memories.
abstract: Anxiety disorders are often associated with an inability to extinguish learned fear responses. The hypocretin/orexin system is involved in the regulation of emotional states and could also participate in the consolidation and extinction of aversive memories. Using hypocretin receptor-1 and hypocretin receptor-2 antagonists, hypocretin-1 and hypocretin-2 peptides, and hypocretin receptor-1 knockout mice, we investigated the role of the hypocretin system in cue- and context-dependent fear conditioning and extinction. Hypocretins were crucial for the consolidation of fear conditioning, and this effect was mainly observed in memories with a high emotional component. Notably, after the acquisition of fear memory, hypocretin receptor-1 blockade facilitated fear extinction, whereas hypocretin-1 administration impaired this extinction process. The extinction-facilitating effects of the hypocretin receptor-1 antagonist SB334867 were associated with increased expression of cFos in the basolateral amygdala and the infralimbic cortex. Intra-amygdala, but neither intra-infralimbic prefrontal cortex nor intra-dorsohippocampal infusion of SB334867 enhanced fear extinction. These results reveal a key role for hypocretins in the extinction of aversive memories and suggest that hypocretin receptor-1 blockade could represent a novel therapeutic target for the treatment of diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder and phobias.
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, C/ Doctor Aiguader 88, 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, PRBB, C/ Doctor Aiguader 88, Barcelona, Spain.
authors.forename: Victòria
authors.initials: V
authors.lastname: Valls-Comamala
authors.affiliation: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Costa
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, C/ Doctor Aiguader 88, Barcelona, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Saravia
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, C/ Doctor Aiguader 88, 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, PRBB, C/ Doctor Aiguader 88, Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Berrendero
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009287:Naphthyridines; D009479:Neuropeptides / Q000378:metabolism*; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000235:genetics / Q000378:metabolism*; D000068797:Orexins; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D014508:Urea / 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; D001583:Benzoxazoles; C497459:Hcrtr1 protein, mouse; C578628:Hcrtr2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D009287:Naphthyridines; D009479:Neuropeptides; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D011619:Psychotropic Drugs; D011725:Pyridines; D014508:Urea