Brain Research Bulletin 130 (2017) 200–210 Contents lists available at ScienceDirect Brain Research Bulletin j ourna l ho me pa g e: www.elsevier.com/locate/brainresbull Research report Activation of cannabinoid receptors elicits antidepressant-like effects in a mouse model of social isolation stress Arvin Haj-Mirzaian a,b,1 , Hossein Amini-Khoei c,d,1 , Arya Haj-Mirzaian a,b , Shayan Amiri a,b , Maria Ghesmati e , Mazyar Zahir a,b , Hamed Shafaroodi f , Ahmad Reza Dehpour a,b,∗ a Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran b Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box, 13145-784, Tehran, Iran c Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran d Department of Physiology and Pharmacology, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran e Department of Microbiology, Islamic Azad University of Lahijan, Lahijan, Iran f Department of Pharmacology and Toxicology, Pharmaceutical Sciences Branch and Pharmaceutical Sciences Research Center, Islamic Azad University, Tehran, Iran a r t i c l e i n f o Article history: Received 29 September 2016 Received in revised form 24 January 2017 Accepted 25 January 2017 Available online 1 February 2017 Keywords: Social isolation stress Depressive-like behavior Cannabinoid receptors Mouse a b s t r a c t Social isolation stress (SIS) paradigm is a chronic stress procedure able to induce profound behavioral and neurochemical changes in rodents and evokes depressive and anxiety-like behaviors. Recent studies demonstrated that the cannabinoid system plays a key role in behavioral abnormalities such as depres- sion through different pathways; however, there is no evidence showing a relation between SIS and the cannabinoid system. This study investigated the role of the cannabinoid system in depressive-like behav- ior and anxiety-like behavior of IC animals. For this purpose, NMRI mice were treated with WIN55, 212-2 (non-selective cannabinoid receptor agonist) and AM-251 (cannabinoid receptor type 1 antagonist) and AM-630 (cannabinoid receptor type 2 antagonist). We found that behavioral abnormality followed by SIS was mitigated after administration of WIN55, 212-2. Also, depressive-like effects induced by SIS were sig- nificantly increased following administration of AM-251 and AM-630. Co-administration of cannabinoid receptor antagonists (AM-251 and AM-630), significantly reversed the antidepressant effect of WIN55, 212-2 in IC animals. Our findings suggest that the cannabinoid system is involved in depressive-like behaviors induced by SIS. We showed that activation of cannabinoid receptors (type 1 and 2) could mitigate depression-like behavior induced by SIS in a mouse model. © 2017 Elsevier Inc. All rights reserved. 1. Introduction Evidences from clinical and pre-clinical studies have demon- strated that early life exposure to environmental and social stressors plays a pivotal role in the development of psychi- atric disorders such as depression (Lupien et al., 2009; Pechtel and Pizzagalli, 2011). In this regards, it has been shown that social isolation stress (SIS) paradigm is a chronic stress pro- cedure able to induce profound behavioral and neurochemical changes in rodents and evokes depressive and anxiety-like behav- iors (Fone and Porkess, 2008; Weiss et al., 2004; Nestler and Hyman, ∗ Corresponding author at: Experimental Medicine Research Center, Tehran Uni- versity of Medical Sciences, P.O. Box 13145-784, Tehran, Iran. E-mail addresses: dehpour@yahoo.com, dehpoura@sina.tums.ac.ir (A.R. Deh- pour). 1 Please note that the first two authors are considered as the first authors. 2010; Koob et al., 1989). Glutaminergic system, nitrergic system, hypothalamic-pituitary-adrenal (HPA) axis are pathways known to mediate the impacts of SIS on psychopathologies like depression (Weiss et al., 2004; Haj-Mirzaian et al., 2015; Amiri et al., 2014). The cannabinoid system comprises the cannabinoid receptors (CB1 and CB2 receptors) and represents an important neuromod- ulator in the central nervous system (CNS) (Devane et al., 1992; Dinh et al., 2004; Gong et al., 2006; Matsuda et al., 1990; Sugiura et al., 1995). Recent studies demonstrated that the cannabinoid sys- tem exerts its antidepressant effects through different pathways including the modulation of HPA axis function (Weidenfeld et al., 1994), regulating the release of neurotransmitters (Domenici et al., 2006; Takahashi and Castillo, 2006) and the modulation of neuro- inflammation (Walter and Stella, 2004). Although, antithesis evidence has shown different effects for cannabinoids on behavior, overall, effects of cannabinoids depend on the doses and time of administration as well as experimental http://dx.doi.org/10.1016/j.brainresbull.2017.01.018 0361-9230/© 2017 Elsevier Inc. All rights reserved.