Investigating the effects of doxycycline in animal models for depression and its possible interaction with cannabidiol and ketamine

• Grant number: 23/09557-0
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Effective date (Start): August 01, 2023
• Effective date (End): June 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Acordo de Cooperação: CNPq
• Principal Investigator: Felipe Villela Gomes
• Grantee: Amanda Juliana Sales
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/01193-9 - Investigating the effects of doxycycline in animal models for depression and its possible interaction with cannabidiol and ketamine, AP.R

Abstract

Stress is a risk factor for the development of psychiatric disorders including schizophrenia and depression. The available treatments are insufficient due to their low efficacy and significant adverse effects. In this sense, new pharmacological approaches have been widely studied. Our research group has been investigating the therapeutic potential of cannabidiol (CBD) for years. CBD, like ketamine, has a rapid and sustained antidepressant-like effect in animal models, it is associated with changes in protein levels related to synaptic plasticity in the prefrontal cortex (PFC). Considering that doxycycline, in a sub-antibiotic dose, showed positive effects in a Parkinson's disease model similar to CBD, we decided to investigate whether doxycycline would also be effective in psychiatric disorders. In a preliminary study, we observed that doxycycline induces a rapid and sustained antidepressant-like effect in animals submitted to the forced swimming test. Like CBD, we also found that doxycycline prevents and attenuates behavioral responses induced by drug abuse. One of the mechanisms described for doxycycline is the reduction in the activity of extracellular matrix metalloproteinases (MMPs). These enzymes are involved in synaptic plasticity, and cocaine use increases their expression in regions associated with positive drug effects. So, this work aims to investigate the possibility of using doxycycline as an "add-on" therapy to the rapid antidepressant effect of CBD and ketamine. Thus, we intend to test the hypothesis that acute treatment with doxycycline, alone or combined with CBD or ketamine, will attenuate behavioral and molecular alterations in the PFC (measured by proteomic analysis and MMPs activity) of animals chronically stressed and/or exposed to locomotor sensitization by ketamine.