The Utility of Prolonged Chronic Unpredictable Stress to Study the Effects of Chronic Fluoxetine, Eicosapentaenoic Acid, and Lipopolysaccharide on Anxiety-Like Behavior and Hippocampal Transcriptomic Responses in Male Rats

Chronic stress is a common trigger of multiple neuropsychiatric illnesses. Animal models are widely used to study stress-induced brain disorders and their interplay with neuroinflammation and other neuroimmune processes. Here, we apply the prolonged 12-week chronic unpredictable stress (PCUS) model to examine rat behavioral and hippocampal transcriptomic responses to stress and to chronic 4-week treatment with a classical antidepressant fluoxetine, an anti-inflammatory agent eicosapentaenoic acid (EPA), a pro-inflammatory agent lipopolysaccharide and their combinations. Overall, PCUS evoked anxiety-like behavioral phenotype in rats, corrected by chronic fluoxetine (alone or combined with other drugs), and EPA. PCUS also evoked pronounced transcriptomic responses in rat hippocampi, involving > 200 differentially expressed genes. While pharmacological manipulations did not affect hippocampal gene expression markedly, Gpr6, Drd2 and Adora2a were downregulated in stressed rats treated with fluoxetine, EPA and fluoxetine + EPA, suggesting their respective protein products (G protein-coupled receptor 6, dopamine D2 receptor and adenosine A2A receptor) as potential evolutionarily conserved targets under chronic stress. Overall, these findings support the validity of rat PCUS paradigm as a useful model to study stress-related anxiety pathogenesis, and call for further research probing how various conventional and novel drugs may (co)modulate behavioral and neurotranscriptomic biomarkers of chronic stress.