DEPRESSION-LIKE BEHAVIOUR IN MICE IS INDUCED BY THE CHRONIC INFLAMMATION AND SYSTEMIC IMMUNE ACTIVATION IN THE MODEL OF COLLAGEN INDUCED ARTHRITIS Anzulović Ž., Hrvačić B., Glojnarić I. and Relković D. Fidelta d.o.o. Prilaz baruna Filipovića 29 Zagreb, HR-10000, Croatia E-mail: Zeljka.Anzulovic@glpg.com Introduction Depression is a severe psychiatric disorder with a high worldwide incidence and low to moderately effective medication available for treatment. A growing body of evidence is now suggesting a strong association between clinical depression and activated immune system. In this study, the hypothesis that chronic systemic activation of immune response could lead to development of depression-like behaviour in mice was tested. Materials and methods Chronic inflammation and depression-like behaviour was investigated in a mouse model of collagen induced arthritis (CIA) in DBA/1J mice. Vehicle-treated CIA mice were compared to healthy controls and animals treated with imipramine and fluoxetine. Depression-like behaviour was assessed via sucrose preference test (SPT) and novelty suppressed feeding test (NSF). Serum levels of three biomarkers previously found to be correlated with major depressive disorder (prolactin; myeloperoxidase, MPO; alpha-1-antitrypsin, A1AT) were also evaluated. Study overview Figure 1. Experimental plan and clinical scores overview Results Lower preference and reduced consumption of sucrose were observed in arthritic mice compared to healthy controls. Imipramine and fluoxetine-treated animals showed reduced consumption of reward compared to vehicle-treated mice. Similarly, NSF test in imipramine-treated group revealed reduced food intake and increased latencies to enter central arena. Serum levels of prolactin, MPO and A1AT were found to be elevated in all CIA-animals. Behavioural tests Anhedonia Biomarkers serum levels Figure 2. Sucrose preference test Each bar represents the percentage of animals per group that reached the preference criterion (chose reward over water in ≥70% of sessions) during the final 17 days of treatment period and the volume of consumed reward per animal for animals that survived the whole experiment on the last day of testing (neg n=10, vehicle n=10, imipramine n=10, fluoxetine n=8 ) Anxiety, hyponeophagia and neophagia Figure 4. A1AT, MPO and Prolactin serum concentration Elevated serum levels in Vehicle and Imipramine-treated animals with CIA in comparison to Negative control Figure 3. Novelty-suppressed feeding Each bar/scatter represents latency data to enter central arena and the volume of consumed reward per animal for animals that survived the whole experiment on the last day of testing (neg n=10, vehicle n=10, imipramine n=9, fluoxetine n=2 ) Conclusion Behavioural tests as well as serum levels of prolactin, MPO and A1AT indicate that systemic inflammation and depression-like behaviour were induced in the mouse CIA model. Behavioural differences between non-treated CIA animals and CIA animals treated with fluoxetine and imipramine observed Sucrose preference : indication of anhedonia in treated animals (more pronounced in Imipramine than in Fluoxetine group) Novelty suppressed feeding: increased latencies to enter central arena and reduced food intake in CIA animals treated with imipramine and fluoxetine in comparison to non-treated CIA and healthy animals. Limited behavioural differences in reward consumption between healthy and vehicle-treated CIA animals as well as indications of anhedonia in imipramine-treated animals could be attributed to specificity of DBA/1J mouse strain. References Singer, P., J. Feldon and B. K. Yee (2009). "Are DBA/2 mice associated with schizophrenia-like endophenotypes? A behavioural contrast with C57BL/6 mice." Psychopharmacology (Berl) 206(4): 677-698. Samuels, Benjamin Adam and René Hen (2011) "Novelty-Suppressed Feeding In The Mouse". Mood And Anxiety Related Phenotypes In Mice: Characterization Using Behavioral Tests, Volume II. Todd D. Gould. 1st ed. Springer Science + Business Media, 2011. 107-121 Papakostas GI1, Shelton RC, Kinrys G, Henry ME, Bakow BR, Lipkin SH, Pi B, Thurmond L, Bilello JA. (2011) "Assessment of a multi-assay, serum-based biological diagnostic test for major depressive disorder: a Pilot and Replication Study“Molecular Psychiatry (2013) 18, 332–339 Poster available online at: www.fidelta.eu