Chronic stimulation of the sigma-1 receptor ameliorates autonomic nerve dysfunction and atrial fibrillation susceptibility in a rat model of depression

Abstract

Aims The present study assessed the effect of Sigma-1 receptor (S1R) stimulation on autonomic nerve dysfunction and atrial fibrillation susceptibility in rat depression models. Methods and Results Male rats were randomly divided into four treatment groups for four weeks: saline (CTL), saline+ intragastric administration of SA4503 (agonist of the S1R, CTS), chronic unpredictable mild stress (CUMS) to produce depression(MDD), and CUMS+ intragastric administration of SA4503 (MDS). After 4 weeks, depression-like behaviors, such as sucrose preference, body weight, and immobility during forced swimming improved in the MDS group. Compared with CTL, MDD showed augmented sympathetic activity, reduced parasympathetic activity, decreased heart rate variability, and significantly lowered S1R expression in the atrium and in hippocampal tissues (all P<0.01). However, the MDS group showed mitigation of most of the above alterations and improved electrical remodeling (all P<0.01). Furthermore, the MDS group showed shortened activation latencies, increases in the effective refractory period, and lower frequency of AF incidence duration and fibrosis compared to MDD (all P<0.01). Conclusions The results indicate that S1R stimulation reduces sympathetic activity and atrial fibrillation susceptibility by improving depressive behaviours, modulating cardiac autonomic nerve balance, lightening nerve remodeling, and up-regulating S1R expression.

The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism

“…Consistent with our previous study, the repolarization of a single cell may affect the behavior of multiple ion currents, resulting in BVR turbulence. It is widely acknowledged that slight changes in ion fluxes in the plateau phase significantly affect the membrane potential and thus the duration of AP (Liu X. et al, 2018). PES or burst stimulation are performed to induce reentry, which may be the one of the main causes of atrial arrhythmias.…”

“…Behavioral measurements consisted of three tests: the sucrose preference test (SPT), forced swimming test (FST), and the body weight test (BWT) (Liu X. et al, 2018).…”

“…Our previous study found that S1R activation produced antiarrhythmic effects with reversed expression of voltage-dependent L-type calcium channels and potassium channels in a rat model of depression. In addition, S1R stimulation reduced sympathetic activity, which may be potential mechanistic contributors (Liu X. et al, 2018).…”

Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology

“…Treatment with a Sigmar1 agonist reversed these effects rescuing the effects of Sigmar1 inhibition ( Ye et al, 2019 ). Similarly, Sigmar1 activation by selective Sigmar1 ligands also protected the depression-induced atrial fibrillation ( Liu et al, 2018b , 2019 ).…”

Revisiting the sigma-1 receptor as a biological target to treat affective and cognitive disorders

“…Rats, after chronic unpredictable mild stress procedure, demonstrated despair (increased immobility in the forced swim test), and anhedonic (decreased sucrose consumption) behaviors ( Chen et al, 2020 ; Liu et al, 2019 ). Chronic treatment with SA4503 or fluvoxamine, sigma-1 receptor agonists, abolished the negative behavioral effects of chronic stress ( Chen et al, 2020 ; Liu et al, 2018 , 2019 ). Moreover, only one-week treatment with SOMCL-668 (an allosteric modulator of sigma-1 receptor) was enough to reverse the stress-induced decrease in the sucrose preference ( Wang et al, 2016 ).…”