Abstract # 1831 Repeated social defeat stress-induced neuroinflammation contributes to later fear sensitization and impaired extinction recall of fear conditioning in mice: Involvement of the endocannabinoid system

Repeated social defeat (RSD) stress promotes myeloid cell trafficking, neuroinflammation and prolonged anxiety-like behavior. RSD could be useful to mimic PTSD-like symptoms in mice. Endocannabinoid (eCB) system molecules are expressed by immune and neuronal cells, modulating their functions, including behavior. The purpose of this study was to test if eCB system activation in mice would attenuate neuroinflammatory and behavioral effects of RSD. To address that, C57BL/6 mice received a nonselective cannabinoid agonist, WIN55,2122 (WIN; 1 mg/kg, i.p.), 30 min prior to each of six social defeat stress exposure. In the next morning, the anxiety-like behavior was evaluated. One week later, independent groups of mice were submitted to the contextual fear conditioning (3 footshock, 0.75 mA, 2s/each). Fear expression and extinction acquisition were evaluated 24 h later and fear extinction recall after additional 24 h. WIN attenuated the RSD-induced immune system and HPA axis activation, neuroinflammation and anxiety-like behavior. Brain CD11b + cells from stressed mice exhibited increased cytokines and eCB-related genes mRNA expression. Moreover, those cells stimulated with LPS ex-vivo presented higher supernatant IL-6. RSD also induced later fear sensitization, impaired extinction recall and increased frontal cortex and hippocampus IL-1 β mRNA expression. WIN attenuated RSD effects. Our data showing that WIN prevents conditioned fear processing alteration following RSD-induced neuroinflammation suggest that the eCB system could be a potential target in stress-related disorders with a neuroinflammatory component, like PTSD.