Prophylactic Ketamine Treatment Promotes Resilience to Chronic Stress and Accelerates Recovery: Correlation with Changes in Synaptic Plasticity in the CA3 Subregion of the Hippocampus.

Adam Krzystyniak,Nirmal Das,Jakub Wlodarczyk,Svitlana Antoniuk,Matylda Roszkowska,Marta Magnowska,Subhadip Basu,Michal Pikula,Monika Zareba-Koziol,Ewa Baczynska

doi:10.3390/ijms20071726

Abstract

Ketamine is an N-methyl-d-aspartate receptor antagonist that has gained wide attention as a potent antidepressant. It has also been recently reported to have prophylactic effects in animal models of depression and anxiety. Alterations of neuroplasticity in different brain regions; such as the hippocampus; prefrontal cortex; and amygdala; are a hallmark of stress-related disorders; and such changes may endure beyond the treatment of symptoms. The present study investigated whether a prophylactic injection of ketamine has effects on structural plasticity in the brain in mice that are subjected to chronic unpredictable stress followed by an 8-day recovery period. Ketamine administration (3 mg/kg body weight) 1 h before stress exposure increased the number of resilient animals immediately after the cessation of stress exposure and positively influenced the recovery of susceptible animals to hedonic deficits. At the end of the recovery period; ketamine-treated animals exhibited significant differences in dendritic spine density and dendritic spine morphology in brain regions associated with depression compared with saline-treated animals. These results confirm previous findings of the prophylactic effects of ketamine and provide further evidence of an association between the antidepressant-like effect of ketamine and alterations of structural plasticity in the brain

Highlights

Major depressive disorder (MDD) is one of the most common psychiatric diseases, with a lifetime prevalence of up to 16.9% in the United States
The present study investigated whether a prophylactic injection of ketamine has effects on structural plasticity in the brain in mice that are subjected to chronic unpredictable stress followed by an 8-day recovery period
Our results showed that ketamine administration (3 mg/kg body weight) 1 h before the chronic unpredictable stress (CUS) procedure caused significant changes in dendritic spine density and morphology in brain regions associated with depression, including the prefrontal cortex and subregions of the hippocampus 3 weeks after administration

Summary

Introduction

Major depressive disorder (MDD) is one of the most common psychiatric diseases, with a lifetime prevalence of up to 16.9% in the United States. It is associated with despair and increases in anxiety and anhedonia [1,2]. Chronic as well as acute severe stress may precipitate or exacerbate depression and multiple studies have reported elevated stress hormones levels in depressed patients and in animal models of depression [3,4] rodents repeatedly infused with corticosterone developed depression-like phenotype [5] and approximately 50–70% of patients with endogenous Cushing syndrome are diagnosed with major depressive disorder [6] which indicates causative relation between stress and the disease. The extent of atrophy is correlated with the duration and severity of symptoms, and such pathogenic changes may persist even after recovery from depression [9,10,11]

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Conclusion