Participation of epigenetics mechanisms in the mediation of the antidepressant-like effect induced by NMDA receptor antagonists

• Grant number: 14/02666-9
• Support type: Scholarships in Brazil - Master
• Effective date (Start): June 01, 2014
• Effective date (End): May 31, 2015
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal researcher: Sâmia Regiane Lourenço Joca
• Grantee: Karina Montezuma
• Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Depression is a major public health problem with high incidence in the world population. However, the currently available antidepressants exhibit a latency of 2-4 weeks to induce an improvement in symptoms and around 45% of the patients do not respond to these drugs, which act by facilitating the monoaminergic neurotransmission . With the search of new targets for treatment of this disorder, has recently been shown that the ketamine, NMDA receptor antagonist, exerts a rapid, robust and long lasting antidepressant effect in animals and patients. On the other hand, the use of this drug for the depression treatment has various side effects. So, the understanding of its mechanism of action could present a significant importance for the development of new and better antidepressants. It is noteworthy that the mechanisms underlying antidepressant action of ketamine appear to be more complicated than simply blocking the NMDA receptor, considering evidence that receptor blockade with MK-801, for example, reduced the immobility time in the forced swim test (FST) in mice for up to 3 hours, but without reproducing the lasting effects of ketamine. Considering this, evidence indicates that some characteristics are important and/or essential for the action of ketamine, as an increased glutamatergic neurotransmission, with consequent activation of AMPA receptors and molecular alterations in the mTOR signaling pathway controlling the induction of intracellular cascades that regulating the proteins synthesis. Thus, the mechanism of action of ketamine seems to interfere with changes in expression of genes related to neural plasticity processes, which can be modulated by epigenetic mechanisms such as DNA methylation, a process carried out by DNA methyltransferases (DNMTs). So, this project aims to test the hypothesis that the rapid antidepressant-like effect induced by treatment with NMDA receptor antagonists (ketamine and MK-801) occurs associated with a decreased in global methylation and DNMTs levels in the prefrontal cortex and hippocampus (dorsal and ventral) of mice and that this reduction is maintained after 7 days only in samples from animals treated with ketamine, as only this drug has sustained antidepressant-like effect .