Involvement of potassium channels in the antidepressant-like effect of venlafaxine in mice Cristiani F. Bortolatto, Cristiano R. Jesse, Ethel A. Wilhelm, Cristina W. Nogueira ⁎ Laboratory of Synthesis, Reactivity, Pharmacological and Toxicological Evaluation of Organochalcogens, Natural Science Institute, Federal University of Santa Maria, Santa Maria, CEP 97105-900, RS, Brazil abstract article info Article history: Received 23 September 2009 Accepted 18 January 2010 Keywords: Venlafaxine Antidepressant-like Potassium channels Forced swim test (FST) Mice Aims: Studies have shown that the acute administration of venlafaxine elicits an antidepressant-like effect in the mouse forced swim test (FST) by a mechanism dependent on the L-arginine–nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) pathway. Because it has been reported that NO activates different types of potassium (K + ) channels in the brain, this study investigated the involvement of K + channels in the antidepressant-like effect of venlafaxine in the mouse FST. Main methods: Male adult Swiss mice were pretreated with different K + channel inhibitors or openers 15 min before venlafaxine administration. After 30 min, the open-field test (OFT) and FST were carried out. Key findings: Intracerebroventricular (i.c.v.) pretreatment of mice with subeffective doses of tetraethylam- monium (TEA, a non-specific inhibitor of K + channels, 25 pg/site), glibenclamide (an ATP-sensitive K + channel inhibitor, 0.5 pg/site), charybdotoxin (a large- and intermediate-conductance calcium-activated K + channel inhibitor, 25 pg/site) or apamin (a small-conductance calcium-activated K + channel inhibitor, 10 pg/site) was able to potentiate the action of a subeffective dose of venlafaxine (2 mg/kg, i.p.). Moreover, the reduction in the immobility time elicited by an effective dose of venlafaxine (8 mg/kg, i.p.) in the FST was prevented by the pretreatment of mice with the K + channel openers cromakalim (10 μg/site, i.c.v.) and minoxidil (10 μg/site, i.c.v.). The drugs used in this study did not produce any change in locomotor activity. Significance: The results demonstrate that the neuromodulatory effects of venlafaxine, via the inhibition of K + channels, are possibly involved in its anti-immobility activity in the mouse FST. © 2010 Elsevier Inc. All rights reserved. Introduction Studies have reported that nitric oxide (NO) can activate different types of potassium (K + ) channels (Bolotina et al. 1994; Armstead 1996; Jeong et al. 2001). Several NO physiological actions are mediated through its interaction with the heme iron of soluble guanylate cyclase (sGC), leading to enzyme activation and subsequent increase in cyclic guanosine monophosphate (cGMP). The K + channel activation by NO is mediated by cGMP (Taniguchi et al. 1993) or by NO itself (Bolotina et al. 1994). The opening of K + channels leads to hyperpolarization of cell membranes, which results in a decrease in cell excitability (Mackinnon 2003). Venlafaxine is a non-tricyclic antidepressant that inhibits serotonin (5-HT) and noradrenaline (NA) reuptake (Berrocoso et al. 2004). Additionally, the involvement of the L-arginine–NO–cGMP signaling pathway in mediating the antidepressant-like activity of venlafaxine in the mouse forced swim test (FST) has been demonstrated, supporting the notion that the inhibition of NO production in the brain may be critical to the action of antidepressants (Dhir and Kulkarni 2007a). Mantovani et al. (2003) have reported that L-arginine–NO–cGMP is an important signaling pathway involved in depression. Although some mechanisms of action of venlafaxine have been reported, additional mechanisms that might be involved in its antidepressant-like effect, including the involvement of K + channels, still need further investigation. Taking into account that K + channels represent one of the major downstream targets regulated by activation of the L-arginine–NO–cGMP pathway, it is possible that the inhibition of NO production elicited by venlafaxine in the FST may reflect an inhibition of K + channels. Studies have suggested the involvement of K + channels in the modulation of depression. In fact, different types of K + channel inhibitors, such as tetraethylammonium (TEA), apamin, charybdotoxin, gliquidone and glibenclamide, were able to produce an antidepressant- like effect in the mouse FST (Galeotti et al. 1999; Kaster et al. 2005), whereas the K + channel openers, such as minoxidil or cromakalim, increased the immobility time, indicating the induction of a depressant- like effect (Galeotti et al. 1999). Life Sciences 86 (2010) 372–376 ⁎ Corresponding author. Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS, Brazil. Tel.: +55 55 32208140; fax: +55 55 32208978. E-mail address: criswn@quimica.ufsm.br (C.W. Nogueira). 0024-3205/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2010.01.013 Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie