Electroacupuncture Combined With Paroxetine Improves Depression-Like Behavior in Rats by Regulating SIRT2/AMPAR in the Hippocampal Dentate Gyrus.

Abstract

BACKGROUND: Evidence from both clinical trials and animal studies indicates that electroacupuncture (EA) combined with antidepressants is more effective and has fewer side effects in the treatment of depression. In this study we investigated the impact of EA combined with paroxetine on improving synaptic ultrastructure and regulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in the treatment of depression. METHODS: The study employed a Chronic Unpredictable Mild Stress (CUMS) depression rat model, incorporating interventions such as paroxetine, electroacupuncture (EA), and their combination, along with a normal control group. Behavioral indicators (weighing, the sucrose preference test, and the open field test) assessed modeling and intervention effects. Nissl staining examined hippocampal neuron number and structure changes. Transmission electron microscopy observed alterations in postsynaptic membrane density and dentate gyrus (DG) neuron mitochondria. Western blotting detected AMPAR levels and changes in sirtuin 2 (SIRT2) pathway-related proteins in the DG. The nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide (NAD/NADH) ratio measured mitochondrial function changes. Immunofluorescence validated SIRT2 and AMPAR co-expression for confirmation. RESULTS: Both EA and EA combined with paroxetine notably alleviated depression-like behaviors, particularly anhedonia-like response, in CUMS-induced rats, with the hippocampal DG identified as a focal area. Transmission electron microscopy revealed increased hippocampal DG synapses and enhanced ultrastructure with the combined treatment. Western blotting and immunofluorescence demonstrated improved mitochondrial function and upregulated glutamate ionotropic receptor AMPA type subunit 1 (GluA1) levels through the activated SIRT2 pathway. CONCLUSIONS: The results suggest that the therapeutic mechanism of EA combined with paroxetine is related to the regulation of the SIRT2/AMPAR pathway in the hippocampal DG of CUMS-induced depressive rats, which subsequently affects synaptic ultrastructure.