Arecoline Alleviates Depression via Gut–Brain Axis Modulation, Neurotransmitter Balance, Neuroplasticity Enhancement, and Inflammation Reduction in CUMS Mice

This study evaluated the antidepressant effects of arecoline, a bioactive alkaloid derived from areca nuts, using a mouse model of depression induced by chronic unpredictable mild stress. Arecoline treatment significantly alleviated depression-like behaviors, including anxiety, anhedonia, and despair, as evidenced by behavioral tests. Mechanistically, arecoline restored serotonin and norepinephrine levels in the brain and serum, reduced pro-inflammatory markers such as IL-1β and LPS in both serum and colon, and enhanced hippocampal neuroplasticity through increased BDNF and PSD-95 expression. Moreover, arecoline modulated gut microbiota composition, particularly enriching beneficial species like Bifidobacterium pseudolongum and Ligilactobacillus murinus, and regulated serum metabolites associated with tryptophan metabolism, neurotransmitter synthesis, and oxidative stress. These findings demonstrate that arecoline exerts its antidepressant effects via a multitargeted approach involving the gut-brain axis, neurotransmitter modulation, and neuroplasticity enhancement. This study highlights arecoline as a promising therapeutic candidate for depression, emphasizing its potential to address both central and peripheral mechanisms.