Rasd2 Mediates Acute Fasting-Induced Antidepressant-Like Effects via Dopamine D2 Receptor Activation in Ovariectomized Mice

Abstract

Background Previous studies have shown that estrogen and acute fasting for 9 hours have antidepressant-like effects, by reducing immobility time in the forced swimming test. Estrogen and acute fasting share a common regulatory gene, Rasd2. RASD2 regulates dopamine D2 receptor (DRD2) transmission, but the role of Rasd2 in the DRD2-mediated antidepressant-like effect of acute fasting has not been examined. Methods In this study, open field test, forced swimming test, tail suspension test and sucrose preference test were used for behavioral assessments. RNA-seq, western blot, enzyme-linked immunosorbent assay and co-immunoprecipitation were used to explore the role of Rasd2 in a depression model induced by ovariectomy, and the antidepressant-like effects of 9-hour fasting. Results The RNA seq results show that acute fasting induced a significant change in Rasd2 gene expression. Depression-like behaviors induced by ovariectomy was associated with decrease in RASD2 and DRD2 protein levels in the hippocampus, and Rasd2 overexpression in the hippocampus alleviated depression-like behaviors and increased DRD2 expression. 9-hour fasting has antidepressant-like effects in ovariectomized mice, by up-regulating the protein levels of RASD2, DRD2, CREB-BDNF, Akt, and estrogen receptor beta, and above effects can be blocked by DRD2 antagonists. Conclusions Our results suggest that Rasd2 and DRD2 play pivotal roles in depression-like behavior induced by ovariectomy. Rasd2 regulates DRD2-mediated antidepressant-like effects of acute fasting in ovariectomized mice. Rasd2 can therefore be postulated to be a potential therapeutic target for depression, and perhaps also a potential predictive marker for depression.

Forced Swimming-Induced Depressive-like Behavior and Anxiety Are Reduced by Chlorpheniramine via Suppression of Oxidative and Inflammatory Mediators and Activating the Nrf2-BDNF Signaling Pathway

“…Serotonergic, dopaminergic, and noradrenergic systems have been demonstrated to play a role in the development of depressive-like behavior [ 7 , 8 ]. Drugs that increase serotonin, noradrenalin [ 9 ], and dopamine [ 10 ] have been found to lessen and restore function in depressed patients.…”