Flores África, Valls-Comamala Victòria, Costa Giulia, Saravia Rocío, Maldonado Rafael, Berrendero Fernando
Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, C/ Doctor Aiguader 88, Barcelona, Spain.
Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.
Neuropsychopharmacology. 2014 Nov;39(12):2732-41. doi: 10.1038/npp.2014.146. Epub 2014 Jun 16.
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.
焦虑症常与无法消除习得的恐惧反应有关。下丘脑泌素/食欲素系统参与情绪状态的调节，也可能参与厌恶记忆的巩固和消除。我们使用下丘脑泌素受体-1和下丘脑泌素受体-2拮抗剂、下丘脑泌素-1和下丘脑泌素-2肽以及下丘脑泌素受体-1基因敲除小鼠，研究了下丘脑泌素系统在线索依赖性和情境依赖性恐惧条件反射及消退中的作用。下丘脑泌素对恐惧条件反射的巩固至关重要，这种作用主要在具有高情绪成分的记忆中观察到。值得注意的是，在获得恐惧记忆后，下丘脑泌素受体-1阻断促进恐惧消退，而下丘脑泌素-1给药则损害这一消退过程。下丘脑泌素受体-1拮抗剂SB334867促进消退的作用与基底外侧杏仁核和边缘下皮质中cFos表达增加有关。杏仁核内注射SB334867可增强恐惧消退，但边缘下前额叶皮质内或背侧海马内注射则无此作用。这些结果揭示了下丘脑泌素在厌恶记忆消退中的关键作用，并表明下丘脑泌素受体-1阻断可能是治疗与恐惧不适当保留相关疾病（如创伤后应激障碍和恐惧症）的新治疗靶点。
