Brain Research Bulletin 82 (2010) 57–64 Contents lists available at ScienceDirect Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull Research report Behavioral, biochemical and cellular correlates in the protective effect of sertraline against transient global ischemia induced behavioral despair: Possible involvement of nitric oxide-cyclic guanosine monophosphate study pathway Vaibhav Gaur, Anil Kumar ∗ Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh 160014, India article info Article history: Received 1 October 2009 Received in revised form 9 January 2010 Accepted 14 January 2010 Available online 1 February 2010 Keywords: Antidepressants Ischemia Mitochondrial dysfunction Oxidative stress Post-stroke depression Sertraline abstract Post-stroke depression (PSD) is one of the psychiatric complications after stroke. Present study was conducted to elucidate the protective effect of sertraline and possible involvement of nitric oxide mech- anism against transient global ischemia induced behavioral despair. Bilateral common carotid artery occlusion was given twice for 5 min at 10 min interval followed by 96 h reperfusion. Ischemia reper- fusion significantly increased immobility period and decreased resistance to lateral push as compared to sham-operated group. Ischemia reperfusion caused significant oxidative damage and mitochondrial enzyme complex (I–III) dysfunction as compared to sham group. Sertraline (5 and 10 mg/kg) treatment significantly reduced immobility period, increased resistance to lateral push, attenuated oxidative dam- age and restored mitochondrial enzyme complex activities as compared to ischemia group. l-Arginine (100 mg/kg) or sildenafil (5 mg/kg) pretreatment with sertraline (5 mg/kg) significantly reversed the pro- tective effect of sertraline. However, l-NAME (10 mg/kg) or 7NI (10 mg/kg) pretreatment with sertraline (5 mg/kg) significantly potentiated their protective effect which were significant as compared to their effect alone. The present study shows that nitric oxide modulation is involved in the protective effect of sertraline. © 2010 Elsevier Inc. All rights reserved. 1. Introduction Stroke is currently one of the leading causes of acquired long- term disability among adult populations worldwide [18]. Stroke survivors commonly develop functional disabilities and cognitive impairment. Broad spectrums of emotional and behavioral dis- turbances are commonly observed in stroke patients. Depression is a common problem among stroke survivors and often poorly acknowledged in clinical practice [5]. The presence of post-stroke depression (PSD) is of considerable clinical relevance owing to its impact on the biological, psychological and social dimensions of stroke survivors and their families. Stroke induced depressive dis- orders affects both middle and aged population [9]. Consequently, a complex relationship between depression and stroke exists in which stroke may predispose to precipitate or perpetuate depres- sive disorders [42]. In animals, several experimental models of focal cerebral ischemia (embolic stroke or middle cerebral artery occlusion) or global cerebral ischemia (two vessel artery occlusion) are used to study the stroke pathogenesis [14]. Various behavioral tests which ∗ Corresponding author. Tel.: +91 172 2534106; fax: +91 172 2541142. E-mail address: kumaruips@yahoo.com (A. Kumar). are sensitive towards depression have already been extensively characterized and validated. The behavioral despair test [32,36], learned helplessness [38], and tail suspension test [41] are few classic tests widely recognized as behavioral paradigms used to assess antidepressant activity of drugs in rodents. However, very few studies have been undertaken to investigate cerebrovascular lesion induced emotional disturbances [46,47]. Researchers have previously investigated nitric oxide synthase (NOS) as a novel target of antidepressant action using mouse forced swimming test (FST), a preclinical behavioral paradigm that is widely used to test compounds for antidepressant activity [7,10]. When animals are exposed to the FST, they typically adopt an immobile posture, which is thought to reflect a state of behavioral despair or helplessness [36]. NOS inhibitor (i.e. N G -nitro-l- arginine) has been demonstrated to display an antidepressant-like behavioral profile in the mouse FST and its effects were reversed by l-arginine (substrate for NOS) pretreatment. This is, consistent with an involvement of NO in this behavioral response [21]. Sertraline [(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro- N-methylnaphthalenamine], a selective serotonin reuptake inhibitor (SSRI) is widely used for the treatment of depression with severe anxiety disorders. SSRIs are known for their high affinity for brain serotonin transporter and very low affinities for adrenergic, histaminergic, opiate, GABA and benzodiazepine 0361-9230/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2010.01.010