Antidepressant Mechanisms and Behavioral Models in Chronic Stress Contexts

Depressive disorders arising from prolonged or unpredictable stress represent a major global health burden. Animal paradigms such as chronic unpredictable mild stress, social defeat and chronic corticosterone administration replicate key features of human depression, including anhedonia, behavioural despair and cognitive impairment. At the molecular level, chronic stress disrupts synaptic connectivity through alterations in glutamatergic signalling, neurotrophin expression and inflammatory pathways. Traditional monoaminergic agents often require weeks to achieve efficacy and fail in a significant proportion of patients, prompting research into rapid-onset therapies. Emerging mechanisms target the NMDA receptor and downstream effectors such as the mammalian target of rapamycin (mTOR) pathway, as well as neuropeptides like pituitary adenylate cyclase-activating polypeptide (PACAP), which converge on regulators of synaptic protein synthesis and plasticity. Behavioural assays—forced swim, tail suspension, sucrose preference and novelty-suppressed feeding tests—allow quantification of antidepressant responses in chronically stressed rodents. An integrated understanding of cellular signalling, synaptic remodelling and animal behavioural readouts is critical to translate novel pharmacological strategies into clinically effective, rapid-acting treatments for stress-induced depression.

Research from Nature Portfolio

Recent foundational studies have delineated key intracellular pathways that mediate rapid and sustained antidepressant effects in chronically stressed mice. One series of experiments compared the traditional Chinese formula Yueju with ketamine and demonstrated that Yueju uniquely engages protein kinase A–cAMP-response element binding protein (PKA–CREB) signalling to sustain hippocampal brain-derived neurotrophic factor (BDNF) upregulation and enduring behavioural improvements. In contrast, ketamine’s acute effects were independent of PKA–CREB, underscoring divergent mechanistic routes to rapid relief. In parallel work, chronic mild stress in mice was shown to dysregulate prefrontal NMDA receptor subunits and inhibit mTOR signalling. Both Yueju and ketamine reversed these changes at early time points, but only Yueju maintained restoration of Akt/mTOR and synaptic protein expression several days later, correlating with prolonged remission of depression-like behaviours. These findings establish NMDA receptor normalisation and mTOR-dependent synaptogenesis as central to fast-acting antidepressant strategies under persistent stress.

Antidepressant Mechanisms and Behavioral Models in Chronic Stress Contexts publication trend

The graph below shows the total number of articles in antidepressant mechanisms and behavioral models in chronic stress contexts across all publications each year (not limited to Nature Index journals).

Technical terms

Chronic unpredictable mild stress (CUMS): A prolonged regimen of varied mild stressors in rodents that induces depression-like behaviours and models human stress-related disorders.

Protein kinase A (PKA): An enzyme that phosphorylates CREB to initiate gene transcription, including upregulation of neurotrophic factors.

cAMP-response element binding protein (CREB): A transcription factor whose activation enhances expression of genes critical for synaptic plasticity and resilience.

Brain-derived neurotrophic factor (BDNF): A neurotrophin that supports neuronal growth, synaptic connectivity and is a key mediator of antidepressant efficacy.

mammalian target of rapamycin (mTOR): A kinase controlling protein synthesis and synaptogenesis, implicated in the rapid actions of certain antidepressants.

N-methyl-D-aspartate (NMDA) receptor: A glutamate receptor involved in synaptic transmission and plasticity, modulation of which can yield rapid antidepressant effects.

Pituitary adenylate cyclase-activating polypeptide (PACAP): A neuropeptide that regulates intracellular cascades involved in rapid antidepressant responses.

Microglial polarization: The process by which microglia adopt pro-inflammatory (M1) or anti-inflammatory (M2) states, influencing neuroinflammation and stress-related mood changes.

References

1. PKA-CREB-BDNF signaling regulated long lasting antidepressant activities of Yueju but not ketamine. Scientific Reports (2016).
2. Involvement of normalized NMDA receptor and mTOR-related signaling in rapid antidepressant effects of Yueju and ketamine on chronically stressed mice. Scientific Reports (2015).
3. Hippocampal PACAP signaling activation triggers a rapid antidepressant response. Military Medical Research (2024).
4. Enhanced antidepressant effects of BDNF-quercetin alginate nanogels for depression therapy. Journal of Nanobiotechnology (2023).
5. Nanoparticulate MgH2 ameliorates anxiety/depression-like behaviors in a mouse model of multiple sclerosis by regulating microglial polarization and oxidative stress. Journal of Neuroinflammation (2023).