Tehran University of Medical Sciences Acta Medica Iranica 0044-6025 56 8 2018 11 26 498 507 EN Saeed Shakiba Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. AND Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AND Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Nazanin Rajai Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AND Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Mehdi Qaempanah Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Nazgol‐Sadat Haddadi Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AND Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Abbas Norouzi-Javidan Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. Reyhaneh Akbarian Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Sattar Ostadhadi Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. AND Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Ahmad-Reza Dehpour Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. AND Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AND Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. 2018 01 05 2018 07 28 Chlorpheniramine, a first-generation antihistamine, is widely used for allergic reactions. Previous studies showed the interaction between antidepressant activity and nitric oxide and cyclic guanosine monophosphate (NO/cGMP) pathway. Thus, we aimed to assess the possible involvement of NO/cGMP pathway in this effect using forced swim test (FST) in male mice. To evaluate the locomotor activity and immobility time, we performed open field test (OFT) and FST on each mouse. Chlorpheniramine was administered intraperitoneally (i.p.) (0.1, 0.3, 1, 10 mg/kg) 30 minutes before FST. To assess the involvement of NO/cGMP pathway, a non-selective nitric oxide synthase (NOS) inhibitor, L-NAME (10mg/kg, i.p.), a selective inducible NOS (iNOS) inhibitor, aminoguanidine (50 mg/kg, i.p.), a selective neural NOS (nNOS) inhibitor, 7-nitroindazole (7-NI, 30 mg/kg, i.p.), a NO precursor, L-arginine (750 mg/kg, i.p.) and a selective phosphodiesterase-5 (PDE-5) inhibitor, sildenafil (5 mg/kg, i.p.) was co-administered with chlorpheniramine. Chlorpheniramine significantly decreased the immobility time at doses of 1mg/kg (P<0.01) and 10 mg/kg (P<0.001). Administration of L-NAME (P<0.01) and 7-NI enhanced the anti-immobility activity of chlorpheniramine (P<0.001), while aminoguanidine did not have any significant effects on the immobility time (P>0.05). Moreover, pretreatment with L-arginine (P<0.01) and sildenafil (P<0.001) significantly reduced the anti-immobility effect of chlorpheniramine. These treatments did not alter the locomotor activity of mice in OFT. Our results revealed that the antidepressant-like effect of chlorpheniramine is mediated through inhibition of NO/cGMP pathway. https://acta.tums.ac.ir/index.php/acta/article/view/6933 https://acta.tums.ac.ir/index.php/acta/article/download/6933/5150