Journal Article

Neuromodulatory Effects of Arecoline on Anxiety-like Behavior in Mice Exposed to Chronic Unpredictable Mild Stress

Fan, Bei, Wang, Fengzhong, Lu, Cong, Cui, Jingwen, Zhang, Xiangfei, Wang, Danyang

2025

Overview

Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the predominant alkaloid of Areca catechu L., displays diverse neuropharmacological properties, yet its role in stress-induced emotional dysfunction has not been fully elucidated. This study examined the anxiolytic-like and neuroprotective effects of arecoline in mice exposed to chronic unpredictable mild stress (CUMS). Arecoline administration markedly improved behavioral outcomes, reflected by increased central exploration in the open-field test, prolonged time in the light compartment, and enhanced open-arm activity in the elevated plus maze. These behavioral benefits were accompanied by normalization of serum corticosterone levels, restoration of hippocampal neurotransmitters, reinforcement of antioxidant enzyme activities, and attenuation of pro-inflammatory cytokines. At the molecular level, arecoline elevated brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), cAMP response element-binding protein (CREB), N-methyl-D-aspartate receptor (NMDAR), and Ca2+/calmodulin-dependent protein kinase II (CaMKII), indicating enhanced synaptic plasticity, while concurrently diminishing oxidative and inflammatory stress. Collectively, the findings suggest that arecoline exerts multifaceted neuroprotective actions under chronic stress by coordinating neuroendocrine modulation, neurotransmitter homeostasis, antioxidant defenses, and synaptic plasticity. This study provides new mechanistic evidence supporting the potential relevance of arecoline as a functional neuroactive compound for managing stress-induced anxiety disorders.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Analysis / Animals / Anti-Anxiety Agents - pharmacology / Antianxiety agents / Antioxidants / Anxiety / Anxiety - drug therapy / Anxiety - etiology / Anxiety - metabolism / Arecoline - pharmacology / Arecoline - therapeutic use / Aspartate / Behavior / Behavior, Animal - drug effects / Brain-derived neurotrophic factor / Brain-Derived Neurotrophic Factor - metabolism / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism / Calmodulin / Corticosterone / Corticosterone - blood / Cyclic AMP Response Element-Binding Protein - metabolism / Cytokines / Disease Models, Animal / Enzymes / Hippocampus - drug effects / Hippocampus - metabolism / Kinases / Lipid peroxidation / Lipids / Male / Methyl aspartate / Mice / Neuronal Plasticity - drug effects / Neuroplasticity / Neurotransmitter Agents - metabolism / Neurotransmitters / Oxidative stress / Oxidative Stress - drug effects / Protein binding / Protein kinases / Receptors, N-Methyl-D-Aspartate - metabolism / Stress, Psychological - complications / Stress, Psychological - drug therapy / Stress, Psychological - metabolism