Antidepressant Mechanisms in Stress-Induced Models
Summary
Stress-induced laboratory models of depression, notably the chronic unpredictable mild stress (CUMS) paradigm, have elucidated multiple pathways through which antidepressant interventions exert their effects. Behavioural restoration in rodents is routinely linked to modulation of monoamine neurotransmitters such as serotonin (5-HT) and noradrenaline, enhancement of neurotrophic factors like brain-derived neurotrophic factor (BDNF), and attenuation of stress-activated intracellular cascades. Emerging evidence also highlights the interplay between the gut–brain axis and central nervous system resilience, with alterations in microbial populations influencing metabolite profiles and neural signalling. At the cellular level, key signalling pathways—including the ERK-CREB and PI3K/Akt cascades—mediate synaptic plasticity and neuronal survival. Moreover, stress can provoke excitotoxic cascades via excess glutamate release, mitochondrial dysfunction and activation of apoptotic pathways. Antidepressant agents, whether small molecules or phytochemicals, counteract these deleterious processes by restoring neurotransmitter balance, stabilising mitochondrial integrity, promoting neurogenesis and recalibrating inflammatory mediators. These multifaceted mechanisms underscore the translational relevance of stress-induced models for identifying novel therapeutic targets and refining clinical strategies for treatment-resistant depression.
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Antidepressant Mechanisms in Stress-Induced Models publication trend
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Technical terms
Chronic Unpredictable Mild Stress (CUMS): A rodent protocol involving varied mild stressors to induce depression-like behaviours and neurochemical alterations.
ERK-CREB Pathway: A signalling cascade where extracellular signal-regulated kinases (ERK) phosphorylate cAMP response element-binding protein (CREB), promoting gene transcription linked to neuronal survival and plasticity.
PI3K/Akt Signalling: A cell survival pathway activated by phosphoinositide 3-kinase (PI3K), leading to phosphorylation of Akt and downstream neuroprotective effects.
Gut–Brain Axis: The bidirectional communication network between the gastrointestinal microbiota and central nervous system, influencing mood and stress responses.
Neurotrophic Factors: Proteins such as brain-derived neurotrophic factor (BDNF) that support neuronal growth, differentiation and synaptic plasticity.
References
- Antidepressant-Like Effects of Cistanche tubulosa Extract on Chronic Unpredictable Stress Rats Through Restoration of Gut Microbiota Homeostasis. Frontiers in Pharmacology (2018).
- Paeoniflorin Ameliorates Chronic Stress-Induced Depression-Like Behaviors and Neuronal Damages in Rats via Activation of the ERK-CREB Pathway. Frontiers in Psychiatry (2019).
- The Anti-depression Effect of Angelicae Sinensis Radix Is Related to the Pharmacological Activity of Modulating the Hematological Anomalies. Frontiers in Pharmacology (2019).
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