Behavioural Brain Research 209 (2010) 249–259 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report -Tocopherol administration produces an antidepressant-like effect in predictive animal models of depression Kelly R. Lobato a , Chandra C. Cardoso a , Ricardo W. Binfaré a , Josiane Budni a , Cristiane L.R. Wagner a , Patrícia S. Brocardo a , Luiz Felipe de Souza b , Caroline Brocardo b , Samira Flesch b , Andiara E. Freitas a , Alcir L. Dafré b , Ana Lúcia S. Rodrigues a,∗ a Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário-Trindade, 88040-900 Florianópolis, SC, Brazil b Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário-Trindade, 88040-900 Florianópolis, SC, Brazil article info Article history: Received 10 June 2009 Received in revised form 27 January 2010 Accepted 1 February 2010 Available online 6 February 2010 Keywords: Forced swimming test Glutathione Tail suspension test -Tocopherol -Tocopheryl phosphate abstract This study investigated the antidepressant potential of -tocopherol, the most active and abundant form of vitamin E, in the forced swim test (FST) and tail suspension test (TST). The acute oral treatment with -tocopherol at the doses of 30 and 100 mg/kg reduced the immobility time in the FST and in the TST. A single i.c.v. administration of -tocopheryl phosphate, a water-soluble analogue of -tocopherol, also reduced the immobility time in the FST (0.1 and 1 nmol/site) and in the TST (0.1 nmol/site). In addition, the long-term treatment (28 days) with -tocopherol (10 mg/kg, p.o.) significantly reduced the immobility time in the FST. Moreover, a subeffective dose of -T (10 mg/kg, p.o.) potentiated the effect of fluoxe- tine (10 mg/kg, p.o.) in the FST. The long-term treatment with -T was able to increase the glutathione (GSH) antioxidant defense system, while the acute treatment was not. The long-term treatment with -tocopherol (10 mg/kg) increased the GSH levels in the hippocampus and in the prefrontal cortex and increased the glutathione peroxidase and glutathione reductase activity in the hippocampus (10 mg/kg) and in the prefrontal cortex (10–100 mg/kg). The long-term treatment with fluoxetine (10 mg/kg, p.o.), a positive control, was also able to increase the GSH levels in the hippocampus, but failed to alter the activity of both enzymes. Besides the specific antidepressant-like effect, long-term, but not the acute treatment with -T, especially in the doses that produced an antidepressant-like effect (10 mg/kg), improved the antioxidant defenses in the mouse hippocampus and prefrontal cortex, two structures closely implicated in the pathophysiology of depression. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Vitamin E is an essential micronutrient present at high concen- trations in green leafy vegetables, vegetable oils, nuts and seeds [14,52]. Natural vitamin E includes two groups of closely related compounds, the tocopherols and tocotrienols, each with four ana- logues [43]. -Tocopherol (-T), the most active and abundant form of vitamin E in human plasma, is the major fat-soluble chain- breaking antioxidant that acts preventing the propagation of free Abbreviations: ANOVA, analysis of variance; DTNB, 5,5-dithiobis-(2- nitrobenzoic acid); FST, forced swimming test; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, reduced glutathione; GSSG, oxidized glutathione; p.o., per os; NADPH, nicotinamide adenine dinucleotide phosphate; TST, tail suspension test; -T, -tocoferol; -TP, -tocopheryl phosphate. ∗ Corresponding author. Tel.: +55 48 3721 5043; fax: +55 48 3721 9672. E-mail addresses: analucia@mbox1.ufsc.br, alsrodri@gmail.com (A.L.S. Rodrigues). radical reactions in membranes and lipoproteins [1,51]. This com- pound also exists in the natural water-soluble form -tocopheryl phosphate, esterified with phosphoric acid, which makes this form of vitamin E an ideal candidate for a number of cellular func- tions, such as oxidant-protected intracellular transport, enzymatic regulation, and cell signaling [25,35,38]. Moreover, -T is part of a complex non-enzymatic antioxidant defense system, which includes glutathione and ascorbic acid [11]. Besides its antioxi- dant activity, several preclinical and clinical studies have shown that -T has pronounced anti-inflammatory and anti-atherogenic properties [20,42,46]. Depression is a chronic, recurring and potentially life threaten- ing mood disorder that affects up to 20% of the world population [7]. It has profound social and economic consequences, with individu- als often experiencing high rates of complicating comorbidities and mortality, like cardiovascular diseases and suicidality, and signifi- cant personal and societal costs due to decreased work productivity and utilization of health care services [36]. Current pharmacological treatment of depression is predominantly focused on the enhance- 0166-4328/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2010.02.002