Behavioral changes induced through adenosine A2A receptor ligands in a rat depression model induced by olfactory bulbectomy.

Karla Margarita Padilla,Fabian López‐Vallejo,Andres Quintanar‐Setephano,Guadalupe García‐Alcocer,Laura Cristina Berumen,Ricardo Miledi

doi:10.1002/brb3.952

Abstract

BackgroundMajor depressive disorders are characterized by their severity and long‐lasting symptoms, which make such disorders highly disabling illnesses. Unfortunately, 50% of major depressive patients experience relapses, perhaps partly because drug research has been performed only in animal models that screen for antidepressant drugs that appear to only ameliorate acute depression symptoms. The bilateral olfactory bulbectomy (OBX) animal model presents the advantage of mimicking the symptoms of chronic depression by means of brain surgery. Adenosine purinergic receptors A2A (A2AR) have been the target of interest in the field of psychiatric diseases. This study aimed to show which A2A receptor ligands exert antidepressive‐like effects in the OBX rat model.MethodsForty Sprague‐Dawley male rats were divided into four groups: control, OBX + vehicle, OBX + ZM 241385, and OBX + adenosine groups. Pharmacological treatment was administered for 14 days, and the rats were examined via the forced swim test (FST), open field test (OFT), and sucrose preference test (SPT).ResultsThe OBX + ZM 241385 group exhibited decreased immobility time in the FST, decreased isolation time in the OFT, and reversed anhedonia behavior in the SPT compared to the vehicle group. However, no significant differences for adenosine treatment were found.Conclusions ZM 241385 administration (2 mg/kg i.p.) restored behavioral changes associated with OBX‐induced depression.

Highlights

Major depressive disorder (MDD) is the most common psychiatric disease, with a prevalence of 16.2% among the world population, and it is the third most significant debilitating public health problem (Mathers & Loncar, 2006)
MDD is distinguished from normal sadness by its severity and duration, where mood is affected for extended periods
Considering the abovementioned works, the focus of this research was the evaluation of the antidepressive effect of the A2AR ligands ZM 241385 and adenosine in an animal model that better represents human depression pathology, similar to the OBX model

Summary

| INTRODUCTION

Major depressive disorder (MDD) is the most common psychiatric disease, with a prevalence of 16.2% among the world population, and it is the third most significant debilitating public health problem (Mathers & Loncar, 2006). New treatments are expected to improve mood disorders and should be studied on appropriate animal models of depression In this context, adenosine purinergic receptors A2A (A2ARs) have been a target of interest in the context of psychiatric diseases due to their broad distribution at the limbic system and their ability to control synaptic plasticity (Ortiz, Ulrich, Zarate, & Machado-Vieira, 2015). Experiments by El Yacoubi and collaborators in 2001 later showed reversed signs of behavioral despair in mice treated with selective A2AR antagonists, for example, SCH 58261 and ZM 241385 (ZM) in addition to genetic inactivation of this receptor (El Yacoubi et al, 2001) It was reported by Kaster et al in 2004 that adenosine is the cause of reversing depressive behavior in mice (Kaster et al, 2004). Considering the abovementioned works, the focus of this research was the evaluation of the antidepressive effect of the A2AR ligands ZM 241385 and adenosine in an animal model that better represents human depression pathology, similar to the OBX model

| MATERIALS AND METHODS

| DISCUSSION

Findings

| CONCLUSION