Effect of NMDA receptor antagonists upon DNA methylation

Author(s)

Karina Montezuma

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2016-09-30

Examining board members

Sâmia Regiane Lourenço Joca; Vanessa Beijamini Harres

• Advisor: Sâmia Regiane Lourenço Joca

Abstract

Although depression presents a high incidence in the world population, currently available antidepressants exhibit a latency of 2-4 weeks to induce a significant improvement of symptoms and around 45% of patients do not respond to these drugs. On the other hand, it has been recently shown that ketamine, a NMDA receptor antagonist, induces a rapid and sustained antidepressant effect in animals and patients. However, the use of this drug for depression treatment has several limitations and, thus, the understanding of the mechanisms underlying its antidepressant action could present a significant importance for the development of new and better therapeutic alternatives. These mechanisms appear to be more complex than the initial blockade of the NMDA receptor, since such blockade by MK-801, for example, reduces the immobility time of mice submitted the forced swimming test (FST) for up to 3 hours, without reproducing the sustained effects of ketamine. Therefore, the cascade of neurochemical events that are initiated after ketamine administration that culminate in the regulation of gene expression and syntehsis of proteins related to neuronal plasticity has been the focus of intense investigation. These genes, in turn, can be modulated by epigenetic mechanisms such as DNA methylation, a process performed by DNA methyltransferase (DNMTs), which has also shown a high relevance to the neurobiology of depression and its treatment. Based on that, the present study aimed at investigating the effects induced by ketamine and MK-801, at doses and treatment protocols that promote antidepressant-like effect in the FST, upon DNA methylation in brain structures of animals submitted or not to the forced swim stress. The first experimental protocols were designed for the analysis of acute and sustained drug-induced antidepressant-like effects: In rats, acute systemic administration of S(+)-Ketamine 10 mg/Kg or MK-801 0.025 mg/Kg 23 hours after the pretest session and 1 hour or 7 days before the test session of FST was investigated. Based on these protocols, the effects of stress (FST) and of treatment with NMDA receptor antagonists were investigated on global DNA methylation levels and DNMT3a and Dnmt3b expression in the rat frontal cortex, ventral and dorsal hippocampus. Both, stress and treatment, induced changes in DNA methylation and DNMT3 expression in some of the brain regions analised. In addition, treatment with MK-801 and ketamine seem to induce differential effects in some areas, which could also be associated with different effects that they present on antidepressant action. (AU)

• FAPESP's process: 14/02666-9 - Participation of epigenetics mechanisms in the mediation of the antidepressant-like effect induced by NMDA receptor antagonists
• Grantee: Karina Montezuma
• Support Opportunities: Scholarships in Brazil - Master