Research report Antidepressant- and anxiolytic-like effects of selective neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole in mice Vallo Volke a, *, Gregers Wegener b,c , Michel Bourin d , Eero Vasar a a Department of Physiology, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia b Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Skovagervej 2, DK-8240 Risskov, Denmark c Centre for Clinical Pharmacology, University of Aarhus, DK-8000 Aarhus C, Denmark d Laboratory of Pharmacology, University of Nantes, 1Rue Gaston Veil, 44035 Nantes Cedex, France Received 15 March 2002; received in revised form 2 September 2002; accepted 4 September 2002 Abstract Various inhibitors of nitric oxide synthase (NOS) have been shown to possess antidepressant- and anxiolytic-like properties in animal models. The aim of this study was to compare the behavioural effects of NOS inhibitor 7-nitroindazole (7-NI) with the more selective neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)imidazole (TRIM) in animal models predictive of antidepressant- and anxiolytic-like activity in order to clarify the role of distinct isoforms of NOS in the regulation of depression and anxiety. Both TRIM (50 mg/kg) and 7-NI (50 mg/kg) decreased the immobility time in the forced swimming test. The magnitude of the effect was comparable to that of the tricyclic antidepressant imipramine (15 mg/kg). The antidepressant-like effect of TRIM was counteracted by pretreatment with L-arginine (250 mg/kg). The systemic administration of TRIM (50 mg/kg), but not 7-NI (up to 50 mg/kg) increased the time spent in the light side of the apparatus in the light /dark compartment test. The anxiolytic-like effect of TRIM was antagonised by pretreatment with L-arginine. Both TRIM and 7-NI decreased the locomotion of animals in the open field and caused motor incoordination on rotarod. These motor side effects were more pronounced in the case of 7-NI and were not diminished by pretreatment with L-arginine. We conclude that neuronal NOS seems to play the key role in the antidepressant- and anxiolytic-like effects of NOS inhibitors. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Nitric oxide; 7-Nitroindazole; TRIM; Forced swimming test; Anxiety; Rotarod 1. Introduction It has become generally accepted that nitric oxide (NO) serves as an important neurotransmitter in the nervous system [2]. NO has been implicated in the regulation of various behavioural, cognitive and emo- tional processes, e.g.: learning, aggression, locomotion, anxiety and depression [12,18,19,25,35]. NO has been suggested recently to have a role in modulating depres- sion. Thus, Harkin et al. [18] and Yildiz et al. [36] have shown that chemically distinct NOS inhibitors produce an antidepressant-like effect in forced swimming test (FST) in mice and rats. Interestingly, depressed patients have increased plasma levels of nitrate, the end-product of NO metabolism [30]. Several studies have demon- strated a potent anxiolytic-like effect of NOS inhibitors in animal models. Thus, NOS inhibitors based on modified arginine molecule have anxiolytic-like effects in the plus-maze test [15,35] and decrease ultrasonic vocalization of rat pups [5]. Also the more selective NOS inhibitor, 7-nitroindazole (7-NI) possesses an anxiolytic- like effect in mice and rats [11,32,37]. Many studies also agree that NOS inhibitors tend to decrease the locomo- tor activity of animals [12,32]. Both neuronal (nNOS) and endothelial (eNOS) iso- forms of NOS are expressed in neurons [10,27]. Studies using knockout mice have suggested that eNOS may play an important role in regulating several neural processes [20,27]. 7-NI is usually referred to as being a selective inhibitor of nNOS in vivo. This assumption may be incorrect as it is based solely on studies showing no effect of the drug on systemic blood pressure [24]. * Corresponding author. Fax:  /372-7-374-332 E-mail address: vallov@ut.ee (V. Volke). Behavioural Brain Research 140 (2003) 141 /147 www.elsevier.com/locate/bbr 0166-4328/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved. PII:S0166-4328(02)00312-1