Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1

• DOI: 10.1016/j.biopha.2022.112925
• Publication Date: 2022-04-09T23:47:55Z
• Authors: Marc Ten-Blanco; África Flores; Inmaculada Pereda...; Fabiana Piscitelli; Cristina Izquierd...; Luigia Cristino; Julián Romero; Cecilia J. Hillard; Rafael Maldonado; Vincenzo Di Marzo; Fernando Berrendero
• Keywords: Extinction (optical mineralogy); Fear-potentiated startle

Anxiety and stress disorders are often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins involved in the modulation of aversive memories, dysregulation this system may contribute aetiology anxiety pathological fear. The mechanisms which orexins regulate unknown. Here we investigated role endogenous cannabinoid impaired extinction induced orexin-A (OXA) male mice. selective inhibitor 2-arachidonoylglycerol (2-AG) biosynthesis O7460 abolished deficits OXA. Accordingly, increased 2-AG levels were observed amygdala hippocampus mice treated with OXA that do not fear, suggesting high endocannabinoid related poor extinction. Impairment was associated expression CB2 receptor (CB2R) microglial cells basolateral amygdala. Consistently, intra-amygdala infusion CB2R antagonist AM630 completely blocked promoted Microglial depletion PLX5622 chow also prevented these deficits. These results show overactivation orexin leads through amygdalar CB2R. This novel mechanism could be relevance for development potential approaches treat diseases inappropriate retention such as post-traumatic disorder, panic phobias.