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

Abstract

<jats:p>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.</jats:p>

Combined hyperforin and lanicemine treatment instead of ketamine or imipramine restores behavioral deficits induced by chronic restraint stress and dietary zinc restriction in mice

“…Moreover, the potency to enhance dendritic spine density and influence dendritic spine morphology are postulated as the primary cellular effects of ketamine and other fast-acting antidepressants (Yang C. et al, 2015;Ng et al, 2018;Zhang et al, 2019;Shao et al, 2021). Similar to results obtained in our previous studies in rats (Pochwat et al, 2020), dietary Zn restriction increased the dendritic spine density in the FC; in the Hp, we noted the opposite effect. These results are in accordance with reported studies showing the effects of clioquinol on dendritic spine density in the hippocampal CA1 region (Frazzini et al, 2018).…”

“…We previously showed that single doses of ketamine and Ro reversed depression-like behaviors induced by dietary Zn restriction in rats ( Pochwat et al, 2020 ). However, little is known about the efficacies of these compounds in conditions where chronic stress and dietary Zn deficiency coexist.…”

“…Chronic stressed and ZnD rodents were characterized by anhedonia (measured by SPT or sucrose intake test (SIT)), increased immobility time (forced swimming test or tail suspension test (TST)), or altered social behaviors ( Whittle et al, 2009 ; Li et al, 2011 ; Castro et al, 2012 ; Mlyniec et al, 2012 ; Mlyniec and Nowak, 2012 ; Pochwat et al, 2014 ; Doboszewska et al, 2015a ; Doboszewska et al, 2015b ; Yang et al, 2018 ). Moreover, the efficacy of classic monoamine-based (chronic administration) or atypical (fast-acting compounds, such as ketamine) antidepressants are similar in the two preclinical paradigms ( Li et al, 2011 ; Doboszewska et al, 2015b ; Pochwat et al, 2020 ). The biochemical effects induced by chronic stress and ZnD in rodents do not fully overlap ( Li et al, 2011 ; Pochwat et al, 2020 ).…”

“…Moreover, the efficacy of classic monoamine-based (chronic administration) or atypical (fast-acting compounds, such as ketamine) antidepressants are similar in the two preclinical paradigms ( Li et al, 2011 ; Doboszewska et al, 2015b ; Pochwat et al, 2020 ). The biochemical effects induced by chronic stress and ZnD in rodents do not fully overlap ( Li et al, 2011 ; Pochwat et al, 2020 ). We emphasize that not much is known about the behavioral and biological effects induced by a combination of chronic stress and ZnD in rodents.…”

Zinc deficiency as a possible risk factor for increased susceptibility and severe progression of Corona Virus Disease 19

“…Disturbed neurogenesis and elevated apoptosis of neuronal cells, which can result in defects in learning and memory, were described during Zn deficiency, as was shown in animals fed on a Zn-deficient diet. Retrospective studies on stroke patients also suggest a clinical significance for serum Zn deficiency (229)(230)(231)(232)(233)(234)(235) . The increase in neuronal apoptosis might involve mitochondrial p53 as well as p53-dependent caspase-mediated mechanisms as shown in vitro (236) .…”