Cyclooxygenase-2 inhibition reduces anxiety-like behavior and normalizes enhanced amygdala glutamatergic transmission following chronic oral corticosterone treatment

Abstract

Chronic stress increases the probability of receiving an anxiety, depression, or chronic illness diagnosis. Pharmacological interventions that reduce the behavioral and physiological effects of chronic stress in animal models may represent novel approaches for the treatment of stress-related psychiatric disorders. Here, we examined the effects of cyclooxygenase-2 (COX-2) inhibition on anxiety-like behaviors and amygdala glutamatergic signaling after chronic non-invasive oral corticosterone (CORT) administration in mice. Treatment with the highly selective COX-2 inhibitor Lumiracoxib (LMX) reversed anxiety-like behavior induced by chronic CORT. Specifically, acute and repeated administration of LMX 5 mg kg −1 reduced chronic CORT-induced anxiety-like behavior measured using the elevated-plus maze, elevated-zero maze, and light-dark box tests. In contrast, LMX did not affect anxiety-like behaviors in naïve mice. Ex vivo electrophysiology studies revealed that repeated LMX treatment normalized chronic CORT-induced increases in spontaneous excitatory glutamatergic currents recorded from anterior, but not posterior, basolateral amygdala neurons. These data indicate COX-2 inhibition can reverse chronic CORT-induced increases in anxiety-like behaviors and amygdala glutamatergic signaling, and support further clinical investigation of selective COX-2 inhibitors for the treatment of affective and stress-related psychiatric disorders.

Cyclooxygenase-2 inhibition prevents stress induced amygdala activation and anxiety-like behavior

“…Acute LMX (5 and 10 mg kg −1 ) did not affect baseline anxiety-like behaviors in naive male mice in the EPM or LD box compared to vehicle (Fig. S2), consistent with previous studies indicating little effect of COX-2 inhibition on anxiety-like behaviors under basal conditions (Morgan et al, 2019). We next examined the effects of COX-2 inhibition on anxiety-like behavior after acute stress exposure in male mice.…”

“…S6). In addition, we have shown, using ex vivo electrophysiological approaches that LMX can normalize the increase in excitatory drive to anterior BLA neurons observed after chronic corticosterone treatment (Morgan et al, 2019). Based on these data, we tested the hypothesis that acute restraint stress exposure would increase the activity of BLA neurons in vivo, and that LMX pretreatment would normalize this increase.…”

“…All studies were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Vanderbilt University Institutional Animal Care and Use Committee (#M1600213-01). Elevated-plus and-zero mazes (EPM and EZM), Open-field test (OFT), and Light-dark box (LD) were performed exactly as described previously (Morgan et al, 2019). To examine the effects of COX-2 inhibition on stress-induced anxiety-like behaviors, we utilized the selective and well-characterized COX-2 inhibitor LMX, which has been shown to reduce PGE 2 levels in human plasma (Mangold et al, 2004).…”

“…Stress is a major risk factor for the development and exacerbation of mood and anxiety disorders (Galatzer-Levy et al, 2018;McEwen, 2004), and recent studies have proposed inflammation as a mechanism by which stress can contribute to depression and anxiety (Fleshner et al, 2017). Interestingly, some clinical studies have shown efficacy of COX-2 inhibitor augmentation in patients with depression (Sethi et al, 2019), and studies using rodent models show inhibition of COX-2 decreases anxiety-like and depressive-like behaviors (Gamble-George et al, 2016;Morgan et al, 2019;Myint et al, 2007;Wang et al, 2018). Despite these data, the mechanisms by which COX-2 inhibition affects behavioral domains relevant to affective disorders are not well understood.…”

Effects of 12 Weeks Cosmos caudatus Supplement among Older Adults with Mild Cognitive Impairment: A Randomized, Double-Blind and Placebo-Controlled Trial

“…Furthermore, we also did not investigate on the bioavailability of flavonoids from CC supplement in human models. Undoubtedly, there are also other possible risk factors that could affect the biochemical profiles and biomarkers such as stress, social activity involvement, dietary practices, and physical activity that should be considered and measured in future studies [ 61 , 62 , 63 , 64 ].…”