Summer Research Description: The targeted enhancement of endocannabinoid (eCB) signaling shows evidence that suggests therapeutic application for a variety of stress related pathological and psychiatric conditions. eCBs are lipid signaling molecules that work to activate several targets, including cannabinoid type 1 and 2 receptors (CB1R and CB2R). The most widely studied eCB molecules are N-arachidonoylethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG). AEA and 2-AG are degraded through fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) metabolic pathways, respectively, and inhibitors of these two enzymes have shown promising pharmacological utility. However, research strongly suggests inhibition of a third pathway involving cyclooxygenase-2 (COX-2) can regulate AEA levels in the brain and peripheral tissues. This study seeks to investigate the behavior linked to ‘substrate-selective’ COX-2 inhibitors (SSCIs), specifically LM-4131, lumiracoxib (LMX), and a reference COX-2 inhibitor, celecoxib, in the reduction of stress-induced anxiety-like behaviors. We will utilize behavioral pharmacology methods to test the hypothesis that COX-2 inhibitors can reduce stress-induced anxiety-like behaviors in mice. If positive results are obtained, we will begin to determine the receptor mechanisms that mediate the anxiolytic effects of COX-2 inhibition. In addition to a behavioral investigation, other techniques will be employed to further compare the mechanisms of these three SSCIs and their effects on the COX-2 metabolic pathway.