Short report 747 Antidepressant-like effects of N-acetyl-L-cysteine in rats Frederico R. Ferreira a , Caroline Biojone a , Sa ˆ mia R.L. Joca b and Francisco S. Guimara ˜es a Oxidative stress disturbances have been reported in depressed patients and in animals submitted to stress. Recent evidence suggests that antidepressants may have antioxidant properties. However, the therapeutic potential of antioxidants as antidepressant drugs has not been systematically investigated. Therefore, this study tested the hypothesis that N-acetyl-L-cysteine (NAC), a cysteine prodrug with powerful antioxidant activity, would possess antidepressant-like properties in the forced swimming test. Male Wistar rats were subjected to 15 min of forced swimming and immediately afterward, 5, and 23 h later received intraperitoneal injections of NAC (5, 15, 50, 150, and 250 mg/kg), imipramine, (15 mg/kg) or vehicle. One hour later they were submitted to the 5 min test swimming session, where immobility time was recorded. Independent groups of animals received the same treatments and their exploratory activity was measured in an open arena for 5 min. NAC (at the doses of 15, 50, and 150 mg/kg) and imipramine induced a significant decrease in immobility time without changing exploratory behavior measured in an open arena. These results suggest that antioxidants such as NAC may have antidepressant effects. Behavioural Pharmacology 19:747–750  c 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins. Behavioural Pharmacology 2008, 19:747–750 Keywords: depression-like behavior, forced swimming test, N-acetyl-L-cysteine, rat a Department of Pharmacology, School of Medicine of Ribeira ˜ o Preto and b Department of Physics and Chemistry, Laboratory of Pharmacology, School of Pharmaceutical Sciences of Ribeira ˜ o Preto, University of Sa ˜ o Paulo, Ribeira ˜o Preto, SP, Brazil Correspondence to Frederico R. Ferreira, MSc, Department of Pharmacology, School of Medicine of Ribeira ˜ o Preto, University of Sa ˜ o Paulo, Ribeira ˜ o Preto, SP, CEP 14049-900, Brazil E-mail: ferreirafr@usp.br Received 15 February 2008 Accepted as revised 23 June 2008 Introduction Major depressive disorder was ranked by the World Health Organization as the fourth greatest cause of global illness burden in the year 2000, and projections indicate that by 2020 it will become the second leading cause of disease worldwide, occupying the first position among psychiatric disorders (Lopez and Murray, 1998; Meyer, 2004). Despite the introduction of tricyclic antidepres- sants to treat depression and more recent advances in chemical antidepressant treatment, including the dis- covery of selective serotonin reuptake inhibitors, the remission rate with antidepressant drugs is frequently not more than 50%. Moreover, approximately 40–60% of antidepressant responders relapse within 4–6 months after stopping the medication (Hirschfeld, 1999; Thase, 2003; Papakostas et al., 2007; Thase et al., 2007). Therefore, the development of more efficient anti- depressant drugs is still necessary. Oxidative stress has been implicated in the pathophysiol- ogy of several diseases, including psychiatric disorders such as schizophrenia, bipolar disorder, and depression. Human studies, for example, have reported a number of oxidative disturbances in depressed patients, including enhanced oxidative damage and decreased antioxidant enzyme levels (Lipton, 1999; Sarandol et al., 2007; Ng et al., 2008). Moreover, preclinical studies have suggested that antioxidants may have antidepressants properties (Pal and Dandiya, 1994; Eren et al., 2007; Zafir and Banu, 2007). Therefore, it has been proposed that antioxidant therapies might have beneficial effects in treating depression. However, no clinical trials of antioxidant therapies in depressed patients have been published to date. Regarding preclinical work, there is only one study using animal models of depression. It showed that glutathione (GSH), a well-known antioxidant, produces antidepressant-like effects in mice submitted to the forced swimming and shock-induced depression tests (Pal and Dandiya, 1994). However, only a single dose (500 mg/g) of the compound was tested. N-acetyl-L-cysteine (NAC) is a cysteine prodrug that has been reported as a promising treatment for several psychiatric disorders. NAC’s biological effects are most frequently attributed to its powerful antioxidant activity, which is achieved through different mechanisms. For example, NAC is able to reduce extracellular cystine to cysteine, it stimulates the synthesis of the major intracellular antioxidant, GSH, enhances glutathione- S-transferase activity, and is a powerful nucleophile capable of scavenging free radicals (De and De, 1993). Despite these antioxidant mechanisms, NAC may also interfere with cystine-glutamate antiporter and, due to increased extracellular glutamate, activate group II metabotropic glutamate receptors (Baker et al., 2007). Despite the studies suggesting a therapeutic potential for NAC in the treatment of Parkinson’s disease 0955-8810  c 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FBP.0b013e3283123c98