Effects of fluoxetine, tianeptine and olanzapine on unpredictable chronic mild stress-induced depression-like behavior in mice Oguz Mutlu a, ⁎, Esen Gumuslu b, 1 , Guner Ulak a, 2 , Ipek Komsuoglu Celikyurt a, 3 , Sibel Kokturk c, 4 , Hale Maral Kır d, 5 , Furuzan Akar a, 6 , Faruk Erden a, 7 a Department of Pharmacology, Faculty of Medicine, Kocaeli University, 41380 Kocaeli, Turkey b Department of Medical Genetics, Faculty of Medicine, Kocaeli University, 41380 Kocaeli, Turkey c Department of Histology and Embriyology, Ordu University Medical Faculty, 52000 Ordu, Turkey d Department of Biochemistry, Faculty of Medicine, Kocaeli University, 41380 Kocaeli, Turkey abstract article info Article history: Received 17 May 2012 Accepted 26 September 2012 Keywords: Depression Unpredictable chronic mild stress Tianeptine Olanzapine Fluoxetine Mice Aims: Tianeptine is an atypical antidepressant drug that has a different mechanism of action than other anti- depressants. Olanzapine is an atypical antipsychotic drug used for the treatment of schizophrenia. The present study was undertaken to investigate effects of chronic administration of tianeptine or olanzapine on unpredictable chronic mild stress (UCMS)-induced depression-like behavior in mice compared to a widely used SSRI antidepressant, fluoxetine. Main methods: Male inbred BALB/c mice were subjected to different kinds of stressors several times a day for 7 weeks and were treated intraperitoneally with tianeptine (5 mg/kg), olanzapine (2.5 mg/kg), fluoxetine (15 mg/kg) or vehicle for 5 weeks (n=7–8 per group). Key findings: All the drugs tested prevented stress-induced deficit in coat state during UCMS procedure, in grooming behavior in the splash test, decreased the attack frequency in the resident intruder test and decreased the immobility time in the tail suspension test. In the open field test olanzapine had anxiolytic-like effects in both stressed and non-stressed mice. Tianeptine, olanzapine and fluoxetine decreased the enhanced levels of plasma ACTH and IL-6. Chronic treatment with tianeptine resulted in a significant increase in both total number and density of BrdU-labeled cells in stressed animals, while fluoxetine and olanzapine had a partial effect. Significance: The results of this study support the hypothesis that tianeptine can be as effective as fluoxetine for the treatment of depression in spite of the differences in the mechanism of action of these drugs. Moreover, olanzapine could be used effectively in psychotic patients with depression. © 2012 Elsevier Inc. All rights reserved. Introduction Depression is a serious emotional disorder with high morbidity and mortality (Kiecolt-Glaser and Glaser, 2002). It is caused by several stress factors and leads to changes in neurotransmitter levels in the brain, important changes in neuronal dendrite structure and function and his- topathological changes in the volume and structure of important brain areas. The atypical antidepressant tianeptine, which has a mechanism of action opposite that of SSRIs, exerts its antidepressant activity by in- creasing serotonin reuptake (Mennini et al., 1987). The commonly used atypical antipsychotic olanzapine, which is proposed to have antidepressant-like activity, exerts its effect via both serotonergic and dopaminergic receptors (Marston et al., 2011; Nemeroff, 2007). Tianeptine, similar to fluoxetine, diminishes the neuronal degenera- tion caused by depression. Tianeptin reverses the effects of chronic stress on brain plasticity in animal depression models (Czéh et al., 2001; Vouimba et al., 2003). Fluoxetine is a selective serotonin (5-HT) reuptake inhibitor, and its antidepressant features are well known (Mutlu et al., 2009). Chronic therapy with both antidepressants and antipsychotics decreases the anhedonic symptoms observed in schizophrenic and depressive patients, reverses cognitive disturbances and increases Life Sciences 91 (2012) 1252–1262 ⁎ Corresponding author at: Department of Pharmacology, Faculty of Medicine, Kocaeli University, 41380 Kocaeli, Turkey. Tel.: +90 262 303 72 50; fax: +90 262 303 70 03. E-mail addresses: oguzmutlu80@hotmail.com (O. Mutlu), dr_esenulak@hotmail.com (E. Gumuslu), gunerulak@yahoo.com (G. Ulak), ikomsu@hotmail.com (I.K. Celikyurt), skokturk@mynet.com (S. Kokturk), hale.maral@isnet.net.tr (H.M. Kır), firuzanakar@gmail.com (F. Akar), faruk.erden@isbank.net.tr (F. Erden). 1 Tel.: +90 506 397 86 59. 2 Tel.: +90 262 303 74 66. 3 Tel.: +90 2623037457. 4 Tel.: +90 505 514 90 25. 5 Tel.: +90 532 600 64 16. 6 Tel.: +90 2623037464. 7 Tel.: +90 262 303 80 05. 0024-3205/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.lfs.2012.09.023 Contents lists available at SciVerse ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie