Ketamine and Ro 25-6981 Reverse Behavioral Abnormalities in Rats Subjected to Dietary Zinc Restriction.

Bartłomiej Pochwat,Bernadeta Szewczyk,Anna Rafało-Ulińska,Gabriel Nowak,Helena Domin

doi:10.3390/ijms21134791

Abstract

Clinical and preclinical studies indicate that zinc (Zn) is an essential factor in the development and treatment of major depressive disorder (MDD). Conventional monoamine-based antidepressants mobilize zinc in the blood and brain of depressed patients as well as rodents. N-methyl-D-aspartate acid receptor (NMDAR) antagonists exhibit antidepressant-like activity. However, not much is known about the antidepressant efficacy of NMDAR antagonists in zinc-deficient (ZnD) animals. We evaluated the antidepressant-like activity of two NMDAR antagonists (ketamine; global NMDAR antagonist and Ro 25-6981 (Ro); selective antagonist of the GluN2B NMDAR subunit) in ZnD rats using the forced swim test (FST) and sucrose intake test (SIT). A single dose of either Ro 25-6981 or ketamine normalized depressive-like behaviors in ZnD rats; however, Ro was effective in both tests, while ketamine was only effective in the FST. Additionally, we investigated the mechanism of antidepressant action of Ro at the molecular (analysis of protein expression by Western blotting) and anatomical (density of dendritic spines by Golgi Cox-staining) levels. ZnD rats exhibited decreased phosphorylation of the p70S6K protein, and enhanced density of dendritic spines in the prefrontal cortex (PFC) compared to control rats. The antidepressant-like activity of Ro was associated with the increased phosphorylation of p70S6K and ERK in the PFC. In summary, single doses of the NMDAR antagonists ketamine and Ro exhibited antidepressant-like activity in the ZnD animal model of depression. Animals were only deprived of Zn for 4 weeks and the biochemical effects of Zn deprivation and Ro were investigated in the PFC and hippocampus. The shorter duration of dietary Zn restriction may be a limitation of the study. However, future studies with longer durations of dietary Zn restriction, as well as the investigation of multiple brain structures, are encouraged as a supplement to this study.

Highlights

Major depressive disorder (MDD) is a serious medical problem that generates enormous economic and social costs globally
Both clinical and preclinical evidence indicates that lower intake of dietary of zinc may be associated with MDD symptoms in humans and depressive-like behaviors in rodents [9,15,19,21]
A few preclinical studies have shown that chronic treatment with classic drugs such as fluoxetine or desipramine reversed the depression phenotype induced by dietary Zn restriction in rats and mice [19,21]

Summary

Introduction

Major depressive disorder (MDD) is a serious medical problem that generates enormous economic and social costs globally. The morbidity associated with this disease has been on the increase [1,2,3] and presents a considerable challenge in terms of effective treatment strategies. There are still gaps in the understanding of the biological mechanisms underlying MDD, with no definitive therapy at the moment. Used monoamine-based antidepressant drugs are not effective in a high percentage of people who suffer from MDD [4]. The crucial biological factors involved in the pathophysiology of MDD are not known. New studies on more effective therapies for MDD and a better explanation of the social and biological causes of this illness are warranted

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Methods

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Conclusion