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Neuropsychopharmacology. 2014 Nov;39(12):2732-41. doi: 10.1038/npp.2014.146. Epub 2014 Jun 16.

The hypocretin/orexin system mediates the extinction of fear memories.

Author information

1
Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, C/ Doctor Aiguader 88, Barcelona, Spain.
2
Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.

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.

PMID:
24930888
PMCID:
PMC4200503
DOI:
10.1038/npp.2014.146
[Indexed for MEDLINE]
Free PMC Article

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