In this study, we investigated the effects of endocannabinoid (eCB) degrading enzyme inhibitors on anxiety-like behavior and brain eCB levels in restraint-stressed mice.
For restraint stress, mice were forced in 50mL syringe for 30 minutes. Mouse brain was separated into the prefrontal cortex (PFC), hippocampus (HC), striatum (ST), periamygdaloid cortex (AM) and medulla oblongata (MO). Brain tissues were homogenized with acetonitrile, which quantified for 2-arachidonoylglycerol (2-AG) or arachidonylethanolamide (AEA) content by UPLC/MS/MS. In addition, we measured anxiety levels of mice in the elevated plus-maze test.
Restraint stress decreased 2-AG and AEA levels in PFC and HC, but not ST, AM, and MO. In the elevated plus-maze test, restrain-stressed mice showed anxiogenic behavior. This anxiogenic behavior was ameliorated by administration of JZL184 (an inhibitor of monoacylglycerol lipase which hydrolyze 2-AG) or URB597 (an inhibitor of fatty acid amide hydrolase which hydrolyze AEA).
These results suggest that restraint stress induces anxiogenic behavior through the region-specific decrease of eCB in PFC and HC. This anxiogenic behaviors were ameliorated by inhibitors of eCB degrading enzyme, which indicates that anxiogenic behavior induced by restraint stress might be due to the reduction of eCB in PFC and HC.