Please cite this article in press as: Calmarza-Font I, et al. Antidepressive and anxiolytic activity of selective estrogen receptor modulators in ovariectomized mice submitted to chronic unpredictable stress. Behav Brain Res (2011), doi:10.1016/j.bbr.2011.10.036 ARTICLE IN PRESS G Model BBR-7366; No. of Pages 4 Behavioural Brain Research xxx (2011) xxx–xxx Contents lists available at SciVerse ScienceDirect Behavioural Brain Research j ourna l ho mepage: www.elsevier.com/locate/bbr Short communication Antidepressive and anxiolytic activity of selective estrogen receptor modulators in ovariectomized mice submitted to chronic unpredictable stress Isabel Calmarza-Font 1 , Natalia Lagunas 1 , Luis M. Garcia-Segura ∗ Instituto Cajal, CSIC, E-28002 Madrid, Spain a r t i c l e i n f o Article history: Received 28 July 2011 Received in revised form 20 October 2011 Accepted 23 October 2011 Available online xxx Keywords: Elevated plus maze Estradiol Forced swim test Raloxifene Tamoxifen a b s t r a c t Estradiol has antidepressive and anxiolytic actions. However, its therapeutic use is limited by its periph- eral effects. Selective estrogen receptor modulators may represent an alternative to estradiol for the treatment of depressive symptoms. Here we report that tamoxifen and raloxifene decrease immobility time in the forced swim test and increases the time spent in open arms in the elevated plus maze in ovariectomized mice submitted to chronic unpredictable stress. © 2011 Elsevier B.V. All rights reserved. Estradiol is known to reduce depressive and anxiety-associated behaviors in laboratory animals [1–5]. However, the use of estra- diol for the treatment of affective disorders in humans is limited by its peripheral effects. Selective estrogen receptor modulators (SERMs), which have antagonistic activity to estrogen receptors (ERs) in some tissues and agonistic activity in other tissues, may represent an alternative to estradiol [6]. Tamoxifen, as a result of its antagonist activity on ERs in breast tumors is often used to treat breast cancer [7]. Raloxifene is also an antagonist of ERs in uterus and breast [8], but has agonistic effects in bone and it is used as a preventive treatment for postmenopausal osteoporosis [9]. In addition to these peripheral effects, SERMs may have estro- genic activity in the brain [10]. For instance, tamoxifen and/or raloxifene have similar effects to estradiol in the reduction of the expression and release of proinflammatory molecules from glial cells [11–13] and in the regulation of glial activation in models of inflammation and brain injury [14,15]. In addition, protective effects of tamoxifen and raloxifene have been detected in ani- mal models of excitotoxicity [16], Alzheimer’s disease [17,18], Parkinson’s disease [19–23], multiple sclerosis [24] and traumatic brain injury [25]. In this study we have assessed whether estra- diol, tamoxifen and raloxifene affect depressive and anxiety-like ∗ Corresponding author at: Instituto Cajal, CSIC, Avenida Doctor Arce 37, E-28002 Madrid, Spain. Tel.: +34 915854729; fax: +34 915854750. E-mail address: lmgs@cajal.csic.es (L.M. Garcia-Segura). 1 These authors contributed equally to this work. behaviors in ovariectomized mice submitted to chronic unpre- dictable stress, a well characterized animal model of depression [26]. C57BL6 female mice (Harlan, Barcelona, Spain) were used. Animals were handled following the European Union guidelines (Council Directive 86/609/EEC) and by procedures approved by our institutional animal care committee (Comité de Bioética, CSIC). They were housed in groups of 4–5 animals per cage on a 12-h light, 12-h dark schedule (lights on 8:00 am) and received food and water ad libitum. Two-month-old animals were subjected to bilateral ovariec- tomy under isoflurane anesthesia. When the animals were 6 months old they were exposed to a chronic unpredictable stress protocol [27] during 4 weeks or left undisturbed. The chronic unpredictable stress protocol was a modified version of the one previously described by Moreau et al. [28] and in our previous experiments has shown to induce depressive and anxiety-like behaviors in ovariectomized mice [29]. The chronic unpredictable stress protocol included stressors such as social isolation, exposure to a predator (rat), continuous room and cage changes, cage tilting, damp sawdust, pairing with an unknown mouse and lights-on overnight. (Table 1) We did not include painful stressors or water and food deprivation, to better resemble psychological stress. In a first experiment we assessed the behavioral effects of the chronic unpredictable stress protocol on ovariectomized animals. Therefore, two groups were compared: ovariectomized animals left undisturbed (ovx group) and ovariectomized animals exposed to chronic unpredictable stress (ovxS experimental group). 0166-4328/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2011.10.036