Hippocampal Over-Expression of Cyclooxygenase-2 (COX-2) Is Associated with Susceptibility to Stress-Induced Anhedonia in Mice

• Published in: International journal of molecular sciences Vol. 23; no. 4; p. 2061
• Main Authors: Strekalova, Tatyana, Pavlov, Dmitrii, Trofimov, Alexander, Anthony, Daniel C, Svistunov, Andrei, Proshin, Andrey, Umriukhin, Aleksei, Lyundup, Alexei, Lesch, Klaus-Peter, Cespuglio, Raymond
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.02.2022; MDPI
• Subjects: anhedonia; Anhedonia - drug effects; Anhedonia - physiology; Animals; Antidepressants; Antidepressive Agents - pharmacology; Behavioral despair; Celecoxib; Celecoxib - pharmacology; chronic stress; Citalopram; Citalopram - pharmacology; COVID-19; COX-2 inhibitors; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Dentate gyrus; Depression - drug therapy; Depression - metabolism; Fear conditioning; Hedonic response; Hindlimb Suspension - physiology; Hippocampal plasticity; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; inducible cyclooxygenase-2 (COX-2); Inflammation; Ischemia; major depression; Male; Markers; Mental depression; Mental disorders; Mice; Mice, Inbred C57BL; mRNA; Overexpression; Rats; Rats, Wistar; Resilience; Selective Serotonin Reuptake Inhibitors - pharmacology; Social interactions; Stress; stress resilience; Stress response; Stress, Psychological - drug therapy; Stress, Psychological - metabolism; Sucrose; Susceptibility; Swimming; Swimming - physiology; Tumor necrosis factor-TNF; mouse; fear conditioning; inducible cyclooxygenase-2 (COX-2); hippocampus; celecoxib; stress resilience; anhedonia; chronic stress; citalopram; major depression
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23042061

The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.