Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1.
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2022
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Biomedicine & Pharmacotherapy
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Abstract
Anxiety and stress disorders are often characterized by an inability to extinguish learned fear responses. Orexins/
hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may
contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which
orexins regulate fear are unknown. Here we investigated the role of the endogenous cannabinoid system in the
impaired fear extinction induced by orexin-A (OXA) in male mice. The selective inhibitor of 2-arachidonoylglycerol
(2-AG) biosynthesis O7460 abolished the fear extinction deficits induced by OXA. Accordingly, increased 2-
AG levels were observed in the amygdala and hippocampus of mice treated with OXA that do not extinguish fear,
suggesting that high levels of this endocannabinoid are related to poor extinction. Impairment of fear extinction
induced by OXA was associated with increased expression of CB2 cannabinoid receptor (CB2R) in microglial cells
of the basolateral amygdala. Consistently, the intra-amygdala infusion of the CB2R antagonist AM630 completely
blocked the impaired extinction promoted by OXA. Microglial and CB2R expression depletion in the amygdala
with PLX5622 chow also prevented these extinction deficits. These results show that overactivation of the orexin
system leads to impaired fear extinction through 2-AG and amygdalar CB2R. This novel mechanism could be of
relevance for the development of novel potential approaches to treat diseases associated with inappropriate
retention of fear, such as post-traumatic stress disorder, panic anxiety and phobias.
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Keywords
Orexin, Fear extinction, Amygdala, Microglia