Participation of DNA methylation in rapid and sustained antidepressant-like effects induced by cannabidiol and ketamine

• Grant number: 18/15896-3
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): June 01, 2019
• Effective date (End): May 31, 2021
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Francisco Silveira Guimaraes
• Grantee: Amanda Juliana Sales
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 17/24304-0 - New perspectives in the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders, AP.TEM

Abstract

Ketamine has been widely studied as a drug with rapid and effective antidepressant action in resistant patients to the available conventional treatments. Recently, we have demonstrated that Cannabidiol (CBD), as well as ketamine, has a rapid and sustained antidepressive effect in different animal models. However, the mechanisms involved in this effect are not yet known. It has been assigned an important role for epigenetic mechanisms, such as DNA methylation, regulated by the DNA methyltransferase enzymes (DNMTs), in the neurobiology of depression and the effect of antidepressant drugs. In fact, stress alters DNA methylation, whereas treatment with DNMT inhibitors (5-AzaD or RG108), as well as with conventional antidepressants, attenuate such modifications in limbic structures associated with depression. However, it is not known whether the behavioral effect of Ketamine and CBD would be associated with changes in the methylation of genes related to stress response and depression. Therefore, this work will test the hypothesis that the acute treatment with these drugs would induce behavioral changes associated with modifications in DNA methylation of different genes related to stress in limbic structures, such as hippocampus and prefrontal cortex. Rats will be submitted to the learned helplessness model (pretest, PT, day 1, stressed group will receive inescapable shocks and the habituated group will not receive shocks) and immediately or six days later will receive acute systemic injection of CBD (30 mg / kg, previously known effective dose), ketamine (15, 30 and 60 mg / kg, effective dose to be determined) or vehicle. Six days after PT (day 7), the animals will be submitted to test session. Therefore the animals will be divided into stressed and habituated and subdivided into 3 groups: acute drug day 1, acute drug day 7 or vehicle. Gene-specific DNA methylation analysis will be performed through the Illumina system, and mRNA levels will be assessed through qPCR-RT.