ORIGINAL PAPER Memantine treatment reverses anhedonia, normalizes corticosterone levels and increases BDNF levels in the prefrontal cortex induced by chronic mild stress in rats Gislaine Z. Réus & Helena M. Abelaira & Roberto B. Stringari & Gabriel R. Fries & Flávio Kapczinski & João Quevedo Received: 23 November 2011 / Accepted: 1 February 2012 / Published online: 11 February 2012 # Springer Science+Business Media, LLC 2012 Abstract Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist and several studies have pointed to the NMDA receptor antagonists as a potential therapeutic target for the treatment of depression. The present study was aimed to evaluate the behavioral and physiological effects of administration of memantine in rats exposed to the chron- ic mild stress (CMS) model. To this aim, after 40 days of exposure to CMS procedure, rats were treated with mem- antine (20 mg/kg) for 7 days. In this study, sweet food consumption, adrenal gland weight, corticosterone levels, and brain-derived-neurotrophic factor (BDNF) protein lev- els in the prefrontal cortex, hippocampus and amygdala were assessed. Our results demonstrated that chronic stress- ful situations induced anhedonia, hypertrophy of adrenal gland weight, and an increase of corticosterone levels in rats, but did not alter BDNF protein levels in the rat brain. Memantine treatment reversed anhedonia and the increase of adrenal gland weight, normalized corticosterone levels and increased BDNF protein levels in the prefrontal cortex in stressed rats. Finally, these findings further support the hypothesis that NMDA receptor antagonists such as mem- antine could be helpful in the pharmacological treatment of depression. Keywords Memantine . BDNF . Chronic mild stress . Anhedonic behavior . Depression Introduction Depression is a mood disorder, which affects up to 20% of the world population (Nestler et al. 2002; Manji et al. 2001). For more than 50 years, drugs that increase the synaptic availability of biogenic amines have been used to treat depression, but these antidepressant drugs require 2–4 weeks (or more) to produce a clinical improvement in depressive symptomatology (Skolnick et al. 2009). In addition, patients have a low (about 30%) remission rate (Krishnan and Nestler 2008). For these reasons new research has been conducted for more effective agents (Feier et al. 2011; Magalhães et al. 2011). There is growing evidence that an increase of glutamatergic neurotransmission is involved with the pathophysiology of depression. In addition, studies have been suggested that NMDA receptor antagonists play an important role in the treatment of depression (Hashimoto 2009, 2011; Skolnick et al. 2009). In fact, patients with depression presented a signif- icant increase of serum levels of glutamate, compared with healthy controls (Kim et al. 1982; Mitani et al. 2006), and several preclinical and clinical studies have demonstrated that NMDA antagonists, such as ketamine, memantine, amanta- dine and others, display antidepressant effects (Berman et al. G. Z. Réus : H. M. Abelaira : R. B. Stringari : J. Quevedo Laboratório de Neurociências and Instituto Nacional de Ciência e Tecnologia, Translacional em Medicina (INCT-TM), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil G. R. Fries : F. Kapczinski Laboratório de Psiquiatria Molecular and Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Centro de Pesquisas, Hospital de Clínicas de Porto Alegre, 90035-003, Porto Alegre, RS, Brazil G. Z. Réus (*) Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil e-mail: gislainezilli@hotmail.com Metab Brain Dis (2012) 27:175–182 DOI 10.1007/s11011-012-9281-2