The involvement of serotonergic system in the antidepressant effect of zinc in the forced swim test Bernadeta Szewczyk a , Ewa Poleszak c , Piotr Wlaź d , Andrzej Wróbel e , Eliza Blicharska f , Agnieszka Cichy g , Małgorzata Dybała g , Agata Siwek g , Lucyna Pomierny-Chamioło g , Anna Piotrowska g , Piotr Brański b , Andrzej Pilc b,h , Gabriel Nowak a,g, ⁎ a Laboratory of Trace Elements Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland b Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland c Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Staszica 4, PL 20-081 Lublin, Poland d Department of Animal Physiology, Institute of Biology, Maria Curie-Skłodowska University, Akademicka 19, PL 20-033 Lublin, Poland e Second Department of Gynecology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland f Department of Analytical Chemistry, Medical University of Lublin, Staszica 6, PL 20-081 Lublin, Poland g Laboratory of Pharmacobiology, Department of Cytobiology and Histochemistry, Collegium Medicum, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland h Institute of Public Health, Collegium Medicum, Jagiellonian University, Grzegórzecka 20, PL 31-531 Krakow, Poland abstract article info Article history: Received 9 September 2008 Received in revised form 30 November 2008 Accepted 15 December 2008 Available online 25 December 2008 Keywords: Antidepressants FST pCPA Ritanserin WAY 100635 Zinc Recent preclinical data indicated the antidepressant-like activity of zinc in different tests and models of depression. The present study investigates the involvement of the serotonergic system in zinc activity in the forced swim test (FST) in mice and rats. The combined treatment of sub-effective doses of zinc (hydroaspartate, 2.5 mg Zn/kg) and citalopram (15 mg/kg), fluoxetine (5 mg/kg) but not with reboxetine (2.5 mg/kg) significantly reduces the immobility time in the FST in mice. These treatments had no influence on the spontaneous locomotor activity. Moreover, while the antidepressant-like effect of zinc (5 mg/kg) in the FST was significantly blocked by pretreatment with inhibitor of serotonin synthesis, p-chlorophenyla- lanine (pCPA, 3×200 mg/kg), 5HT-2 A/C receptor antagonist, ritanserin (4 mg/kg) or 5HT-1A receptor antagonist, WAY 1006335 (0.1 mg/kg), the zinc-induced reduction in the locomotor activity was not affected by these serotonin modulator agents. These results indicate the specific involvement of the serotonergic system in antidepressant but not the motion behavior of zinc in mice. Also, an increase in the swimming but not climbing parameter of the rat FST observed following zinc administration (2.5 and 5 mg Zn/kg) indicates the serotonin pathway participation. This present data indicates that the antidepressant-like activity of zinc observed in the FST involves interaction with the serotonergic system. © 2008 Elsevier Inc. All rights reserved. 1. Introduction Zinc is a trace element essential for normal brain function (Takeda, 2000). Zinc is present in specific regions of the brain including the hippocampus, amygdala and cortex (Frederickson et al., 2005). Zinc seems to modulate neuronal excitability (Smart et al., 1994; Frederickson et al., 2005) and is also thought to play an important role in synaptic plasticity (Li et al., 2001). Zinc can also function as a signaling molecule modulating protein function (Haase and Maret, 2005; Krezel et al., 2007). Dietary zinc deprivation influences zinc homeostasis in the brain and leads to behavioral disturbances, such as anorexia, dysphoria, depression, aggression, impaired learning and cognitive function (Takeda, 2000; Takeda et al., 2008; Tassabehji et al., 2008) and some neurological disorders (Takeda, 2000; Mathie et al., 2006). Recent data indicated that zinc is implicated in the pathophy- siology of depression and the mechanism of action by antidepressant drugs. Preclinical studies showed the antidepressant-like activity of zinc in tests and models of depression. Zinc was active in the forced swim test and tail suspension test (Kroczka et al., 2000, 2001; Nowak et al., 2003a,b; Rosa et al., 2003) and enhanced the antidepressant activity of classical antidepressants (imipramine and citalopram) in the forced swim test (Kroczka et al., 2001; Szewczyk et al., 2002; Rosa et al., 2003). Zinc was also active in several models of depression such as: olfactory bulbectomy (Nowak et al., 2003b); chronic unpredictable stress (Cieslik et al., 2007) and chronic mild stress (Sowa-Kućma et al., 2008). Moreover, several clinical studies indicated that major Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 323–329 Abbreviations: i.p., intraperitoneally; CIT, citalopram; FX, fluoxetine; RB, reboxetine; RIT, ritanserin; WAY, WAY 1006335; pCPA, p-chlorophenylalanine; NMDA, N-methyl-D- aspartate; BDNF, brain-derived neurotrophic factor; FST, forced swim test. ⁎ Corresponding author. Laboratory of Trace Elements Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland. E-mail address: nowak@if-pan.krakow.pl (G. Nowak). 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.12.011 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnpbp