Behavioural Pharmacology Chronic treatment with celecoxib reverses chronic unpredictable stress-induced depressive-like behavior via reducing cyclooxygenase-2 expression in rat brain Jian-You Guo a, ⁎, Chang-Yu Li b , Ye-Ping Ruan b , Meng Sun a , Xiao-Li Qi a , Bao-Sheng Zhao c , Fei Luo a, ⁎ a Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences,10A Datun Road, Chaoyang District, Beijing 100101, PR China b Zhejiang Chinese Medical University, Hangzhou 310053, PR China c Beijing University of Chinese Medicine, Beijing 100029, PR China abstract article info Article history: Received 24 January 2009 Received in Revised form 17 March 2009 Accepted 31 March 2009 Available online 6 April 2009 Keywords: Celecoxib Depressive-like behavior Chronic unpredictable stress Cyclooxygenase-2 Prostaglandin E2 Recent clinical trails reported that adjunctive cyclooxygenase (COX)-2 inhibition with celecoxib is beneficial in treating depression. However, another clinical study showed celecoxib did not have inhibitory effect of COX-2 in human brain when given at a therapeutic dose. Therefore, whether celecoxib is exerting its influence through COX inhibition or by some other mechanism remains unclear. The present study further investigated the effect of celecoxib on COX-2 expression, prostaglandin E 2 (PGE 2 , a major COX-2-mediated inflammatory mediator) concentration and the depressive-like behaviors in rats. Celecoxib was admini- strated by oral gavage to naive rats (16 mg/kg) or stressed rats (2, 8, 16 mg/kg, respectively) for 21 days, or to stressed rats for a single dose (16 mg/kg). The results showed that 21 days chronic unpredictable stress induced depressive-like behaviors and increased the COX-2 expression and PGE 2 concentration in rat brain. Chronic treatments with celecoxib alleviated the depressive-like behavior and reversed the levels of COX-2 expression and PGE 2 concentration in stressed rat in a dose-dependent manner. Celecoxib also improved the emotional state and decreased COX-2 expression and PGE 2 concentration in naive rats. In addition, a single dose of celecoxib treatment reversed COX-2 expression and PGE 2 concentration, but didn't alter the depressive-like behavior in stressed rat. These results suggest that COX-2 enzyme might play a key role in pathophysiology of depression. Furthermore, these data indicate that chronic celecoxib treatment reverse chronic unpredictable stress-induced depressive-like behavior might via reducing COX-2 enzyme in brain, and the selective COX-2 inhibitors could be developed as potential remedies for the management of depression. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Depression is a common and debilitating disorder for which current treatments are inadequate. The pathogenesis of depression is not well understood. Current antidepressants, which target mono- amines, only produce remission in 30% of patients (McNally et al., 2008). Part of the problem lies in the fact that the pathophysiology of depression has not been elucidated, and treatments are based on empirical data, not mechanisms of action. Increasing amounts of data suggest that inflammatory responses have an important role in the pathophysiology of depression. Depressed patients have been found to have higher levels of proinflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules (Dantzer et al., 2008; Raison et al., 2006). Arachidonic acid derivatives such as prostaglandins play an important role in the inflammatory response (Pace et al., 2007). Cyclooxygenase (COX) is a rate-limiting enzyme in the metabolism of arachidonic acid to prostaglandins. COX exists mainly in two distinct isoforms (COX-1 and COX-2). The importance of COX-2 in depressive pathology is highlighted by recent findings demonstrating that the inflammatory enzyme mediated many of the central effects of psychologically relevant stressors (Madrigal et al., 2003). Studies indicated that 2–6 h of immobilization stress caused an enhancement of COX-2 protein expression in cortex and hippocampus (Lukiw and Bazan, 1997; Madrigal et al., 2002, 2003).Recently, hippocampal upregulation of the COX-2 mRNA has been demonstrated in a rat model of depression (Cassano et al., 2006). Clinical trails reported that adjunctive COX-2 inhibition with celecoxib is beneficial in treating depression (Muller et al., 2006; Nery et al., 2008). In addition, chronic administration of lamotrigine (a novel antimanic drug) can decrease brain COX-2 expression (Lee et al., 2008), which may account in part for their efficacy in depression. However, Dembo et al. (2005) shown that celecoxib does not reach COX-2 inhibitory levels in human brain when given at a therapeutic dose. Therefore, whether celecoxib is exerting its influence through COX inhibition or some other mechanism remains to be determined. Celecoxib have shown to improve the behavioral and immune changes in the olfactory bulbectomised rat model (Myint et al., 2007). As chronic unpredictable stress acts as a predisposing and participating European Journal of Pharmacology 612 (2009) 54–60 ⁎ Corresponding authors. Tel.: +86 10 64850859; fax: +86 10 64844991. E-mail addresses: guojy@psych.ac.cn (J.-Y. Guo), luof@psych.ac.cn (F. Luo). 0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2009.03.076 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar