Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits
promoted by orexin-A/hypocretin-1
Abstract
Background and purpose: Anxiety is 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 remain
unknown. Experimental approach: We investigated the role of the
endogenous cannabinoid system in the impaired fear extinction induced by
orexin-A (OXA) in male mice. Behavioural pharmacology, neurochemical,
molecular and genetic approaches were used. Key results: 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. Conclusions and
implications: We reveal that overactivation of the orexin system leads
to impaired fear extinction through 2-AG and amygdalar CB2R. This novel
mechanism may pave the way towards novel potential approaches to treat
diseases associated with inappropriate retention of fear, such as
post-traumatic stress disorder, panic anxiety and phobias.