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

Tatyana Strekalova*, Dmitrii Pavlov, Alexander Trofimov, Daniel C Anthony, Andrei Svistunov, Andrey Proshin, Aleksei Umriukhin, Alexei Lyundup, Klaus-Peter Lesch, Raymond Cespuglio

*Corresponding author for this work

Research output: Contribution to journalArticleAcademic

Abstract

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.

Original languageEnglish
Article number2061
Number of pages22
JournalInternational journal of molecular sciences
Volume23
Issue number4
DOIs
Publication statusPublished - 13 Feb 2022

Keywords

  • Anhedonia/drug effects
  • Animals
  • Antidepressive Agents/pharmacology
  • Celecoxib/pharmacology
  • Citalopram/pharmacology
  • Cyclooxygenase 2/metabolism
  • Depression/drug therapy
  • Hindlimb Suspension/physiology
  • Hippocampus/drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Rats
  • Rats, Wistar
  • Serotonin Uptake Inhibitors/pharmacology
  • Stress, Psychological/drug therapy
  • Swimming/physiology
  • fear conditioning
  • celecoxib
  • AMPA-RECEPTORS
  • mouse
  • MESSENGER-RNA
  • stress resilience
  • ANIMAL-MODELS
  • citalopram
  • UP-REGULATION
  • major depression
  • INDUCIBLE CYCLOOXYGENASE
  • hippocampus
  • INHIBITOR CELECOXIB
  • DEPRESSIVE SYMPTOMS
  • PREFRONTAL CORTEX
  • inducible cyclooxygenase-2 (COX-2)
  • NONSTEROIDAL ANTIINFLAMMATORY DRUGS
  • anhedonia
  • DOUBLE-BLIND
  • chronic stress

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