ro-25-6981 and Depressive-Disorder--Major

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.

Topics: Analgesics; Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Depressive Disorder, Major; Diet; Disease Models, Animal; Ketamine; Male; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Zinc

Alcohol use disorder (AUD) and major depressive disorder (MDD) are prevalent, debilitating, and highly comorbid disorders. The molecular changes that underlie their comorbidity are beginning to emerge. For example, recent evidence showed that acute ethanol exposure produces rapid antidepressant-like biochemical and behavioral responses. Both ethanol and fast-acting antidepressants block N-methyl-D-aspartate receptor (NMDAR) activity, leading to synaptic changes and long-lasting antidepressant-like behavioral effects. We used RNA sequencing to analyze changes in the synaptic transcriptome after acute treatment with ethanol or the NMDAR antagonist, Ro 25-6981. Ethanol and Ro 25-6981 induced differential, independent changes in gene expression. In contrast with gene-level expression, ethanol and Ro 25-6981 produced overlapping changes in exons, as measured by analysis of differentially expressed exons (DEEs). A prominent overlap in genes with DEEs indicated that changes in exon usage were important for both ethanol and Ro 25-6981 action. Structural modeling provided evidence that ethanol-induced exon expression in the NMDAR1 amino-terminal domain could induce conformational changes and thus alter NMDAR function. These findings suggest that the rapid antidepressant effects of ethanol and NMDAR antagonists reported previously may depend on synaptic exon usage rather than gene expression.

Topics: Alcoholism; Alternative Splicing; Animals; Antidepressive Agents; Comorbidity; Depressive Disorder, Major; Ethanol; Exons; Gene Expression; Hippocampus; Male; Mice, Inbred C57BL; Models, Animal; Phenols; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Transcriptome

Topics: Animals; Antidepressive Agents; Brain; Brain Mapping; Depressive Disorder, Major; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Ketamine; Magnetic Resonance Imaging; Male; Nonlinear Dynamics; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Wakefulness