Endocannabinoid modulation of predator stress-induced long-term anxiety in rats
Individuals who experience life-threatening psychological trauma are at risk of developing a series of chronic neuropsychiatric pathologies that include generalized anxiety, depression and drug addiction. The endocannabinoid system has been implicated in the modulation of these responses by regulating the activity of the amygdala and the hypothalamic-pituitary-adrenal axis. However, the relevance of this signaling complex to the long-term consequences of traumatic events is unclear. Here, we use an animal model of predatory stress-induced anxiety-like behavior to investigate the role of the endocannabinoid system in the development of persistent anxiety states. Our main finding is that rats exposed to the fox pheromone 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a life-threatening stimulus for rodents, display a marked and selective increase in the mobilization of the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), in the amygdala. This effect lasts for at least 14 days after the stress has occurred. Additionally, systemic or local pharmacological inhibition of monoacylglycerol lipase (MGL) – a lipid hydrolase that degrades 2-AG in presynaptic nerve terminals – elevates 2-AG levels and suppresses the anxiety-like behavior elicited by exposure to TMT. In addition, peripherally restricted pharmacological inhibition of fatty acid amid hydrolase (FAAH) – the enzyme that degrades anandamide – also suppresses the anxiety-like behavior elicited by exposure to TMT. The results suggest that predator threat triggers long-term changes in 2-AG-mediated endocannabinoid signaling in the amygdala, and there is a peripheral endocannabinoid component that influences long-term anxiety states. Overall our findings indicate that pharmacological interventions targeting MGL or FAAH might provide a therapeutic strategy for the treatment of chronic brain disorders initiated by trauma.