Exploring Corticosterone-Induced Depression Models: Mechanisms, Therapeutic Interventions, and Implications for Treatment

Abstract

Corticosterone, a steroid hormone produced in the adrenal cortex, plays a crucial role in stress response and has been implicated in the pathophysiology of depression. This review synthesizes recent findings on the effects of corticosterone in various animal models of depression, highlighting its impact on behavior and neurochemical alterations. Chronic administration of corticosterone induces depressive-like symptoms in multiple species, including rodents and birds, through mechanisms involving the hypothalamic-pituitary-adrenal (HPA) axis dysregulation and the modulation of brain-derived neurotrophic factor (BDNF) levels. Pharmacological interventions such as resveratrol, curcumin, metabotropic glutamate receptor antagonists, liraglutide, and thymol have shown promise in ameliorating these symptoms by restoring neuroplasticity, regulating HPA axis function, and enhancing BDNF signaling. Additionally, studies on the consistency of corticosterone levels across species underscore the role of hormonal plasticity in behavioral outcomes and underscore complexities in hormonal regulation. The corticosterone-induced depression models offer valuable insights into potential therapeutic strategies and the biological underpinnings of depression, ultimately guiding the development of more effective treatments, particularly for disorders characterized by HPA axis dysregulation.

Keywords

Introduction

Corticosterone is a steroid hormone produced in the adrenal cortex, a part of the adrenal glands located atop the kidneys. ⁽¹⁾ It plays a crucial role in regulating energy metabolism, immune responses, and stress reactions in various species, including amphibians, reptiles, rodents, and birds. In humans, however, cortisol serves as the primary glucocorticoid, with corticosterone acting mainly as an intermediate in the synthesis of aldosterone, a mineralocorticoid involved in sodium and potassium balance.⁽²⁾  Corticosterone is synthesized from pregnenolone through a series of enzymatic steps. In humans, it is converted to aldosterone by the enzyme aldosterone synthase, which is present only in the mitochondria of glomerulosa cells in the zona glomerulosa, the outermost layer of the adrenal cortex. ⁽³⁾

Mechanism Of Coricosterone:

Synthesis and Release:        

Corticosterone is synthesized from cholesterol through a multi enzyme process known as steroidogenesis. Adrenocorticotropic hormone (ACTH) stimulates the adrenal glands, leading to the production of corticosterone.⁽⁴⁾This process involves the activation of protein kinase A (PKA), which phosphorylates proteins such as hormone-sensitive lipase (HSL) and steroidogenic acute regulatory protein (StAR).⁽⁵⁾These modifications enhance the availability of cholesterol and its transport into the mitochondria, where it is converted into pregnenolone by the enzyme side-chain cleavage cytochrome P450 (P450scc). Subsequent enzymatic reactions within the mitochondria and endoplasmic reticulum lead to the synthesis of corticosterone. ⁽⁶⁾

Mechanism of Action:

Corticosterone exerts its effects by binding to intracellular glucocorticoid receptors (GRs), which are part of the nuclear receptor family of ligand-activated transcription factors.⁽⁷⁾ Upon binding, the corticosterone-GR complex undergoes a conformational change, allowing it to translocate into the cell nucleus.⁽⁸⁾ Within the nucleus, the complex binds to glucocorticoid response elements (GREs) on DNA, influencing the transcription of target genes.⁽⁹⁾ This interaction can lead to either transactivation (upregulation) or trans repression (downregulation) of gene expression, thereby modulating various physiological processes. ⁽¹⁰⁾

Physiological Effects:

In species where corticosterone is the primary glucocorticoid, it plays a crucial role in regulating energy metabolism, immune responses, and stress reactions. ⁽¹¹⁾ In humans, while corticosterone has weak glucocorticoid and mineralocorticoid potencies, it is important mainly as an intermediate in the steroidogenic pathway from pregnenolone to aldosterone. Aldosterone, synthesized from corticosterone, is a key regulator of sodium and potassium balance, influencing blood pressure and fluid balance. Understanding the synthesis and mechanism of action of corticosterone provides insight into its role in various physiological processes and its significance in the endocrine system. ⁽¹²⁾

Experimental Increase in Corticosterone Levels Improves Subsequent Male Survival

In reptiles, corticosterone levels have been linked to survival probabilities. For instance, studies on Galápagos marine iguanas have shown that corticosterone levels can predict survival during El Niño events, highlighting the hormone's role in stress response and survival. Additionally, research on female lizard morphs has demonstrated that corticosterone levels are associated with survival outcomes. In the species Utastansburiana, females with higher corticosterone levels exhibited better survival rates, suggesting that corticosterone plays a crucial role in fitness and survival in natural settings. These findings underscore the complex role of corticosterone in stress response, behaviour, and survival across different species. ⁽¹³⁾

When can corticosterone levels be consistently replicated?

Hormones are pivotal in integrating internal and external cues, influencing life-history decisions, and modulating individual behavior and physiology. Understanding the consistency of endocrine traits within and among individuals is essential for determining whether hormonal traits can reliably predict phenotypes subject to selection.A study on free-living passerines, specifically great tits (Parus major) and tree swallows (Tachycineta bicolor), examined the repeatability of plasma corticosterone concentrations over multiple years. The researchers found that baseline corticosterone concentrations were repeatable within the breeding season for both sexes of great tits and for female tree swallows. However, these concentrations were not repeatable across different seasons or years. Additionally, stress-induced corticosterone levels in great tits were not repeatable in either sex.⁽¹⁴⁾ These findings suggest that both baseline and stress-induced plasma corticosterone concentrations are relatively plastic traits, with individuals differing in their degree of trait plasticity, thereby affecting their behavioral and physiological responses to various challenges. In contrast, a study on house sparrows (Passer domesticus) found that individual variation in baseline corticosterone concentrations before and during breeding, as well as their seasonal dynamics, predicted reproductive success. This indicates that individual variation in absolute concentrations and in plasticity is functionally significant and may be a target of selection. These studies highlight the complexity of hormonal trait consistency and its implications for individual fitness and evolutionary processes. While some hormonal traits exhibit plasticity and may vary with environmental conditions, others show consistency that can influence reproductive success and survival. Understanding this balance is crucial for comprehending how hormonal regulation shapes individual phenotypes and evolutionary outcomes.⁽¹⁵⁾

"A mouse model of depression created through repeated corticosterone administration."

Recent research has explored the antidepressant-like effects of resveratrol, a naturally occurring polyphenol, in a mouse model of depression induced by chronic corticosterone (CORT) administration. In this model, mice received daily subcutaneous injections of 40 mg/kg CORT for 21 days, leading to depressive-like behaviors such as reduced sucrose consumption and increased immobility in the forced swim and tail suspension tests. Additionally, these mice exhibited elevated serum corticosterone levels and decreased hippocampal brain-derived neurotrophic factor (BDNF) levels. ⁽⁵⁾ Treatment with resveratrol significantly ameliorated these behavioral and biochemical alterations. Specifically, resveratrol reversed the depressive-like behaviors and restored hippocampal BDNF levels. The study suggests that resveratrol's antidepressant-like effect may be mediated by rectifying stress-induced hypothalamic-pituitary-adrenal (HPA) axis dysfunction and upregulating hippocampal BDNF levels.⁽⁵⁾ These findings indicate that resveratrol may offer therapeutic potential for depression, particularly in cases associated with HPA axis dysregulation. However, further research is necessary to fully understand the mechanisms underlying its effects and to evaluate its efficacy in clinical settings. ⁽⁵⁾

"Curcumin alleviates corticosterone-induced depressive behavior and restores brain BDNF levels in rats."

Recent research has investigated the antidepressant-like effects of curcumin, a naturally occurring polyphenol, in a rat model of depression induced by chronic corticosterone (CORT) administration. In this model, rats received daily subcutaneous injections of 40 mg/kg CORT for 21 days, leading to depressive-like behaviours such as reduced sucrose consumption and increased immobility in the forced swim test. Additionally, these rats exhibited decreased brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus and frontal cortex. ⁽¹⁶⁾ Treatment with curcumin significantly ameliorated these behavioural and biochemical alterations. Specifically, curcumin reversed the depressive-like behaviours and restored BDNF levels in the hippocampus and frontal cortex. The study suggests that curcumin's antidepressant-like effect may be mediated by increasing BDNF expression in these brain regions. ⁽¹⁶⁾ These findings indicate that curcumin may offer therapeutic potential for depression, particularly in cases associated with HPA axis dysregulation. However, further research is necessary to fully understand the mechanisms underlying its effects and to evaluate its efficacy in clinical settings. ⁽¹⁷⁾

"Antagonists of metabotropic glutamate 2/3 receptors enhance behavior and correct prefrontal dopaminergic changes in the chronic corticosterone-induced depression mouse model."

The study shared explores the potential antidepressant-like effects of metabotropic glutamate receptor 2/3 (mGlu2/3) antagonists in a chronic corticosterone-treated mouse model of depression, which is often used to simulate treatment-resistant depression. Here's a breakdown of the findings: ⁽¹⁸⁾

1. Effect on Immobility in the Forced Swim Test (FST):
   • mGlu2/3 antagonists (MGS0039 and LY341495) reduced the increased immobility time in the FST of corticosterone-treated mice, indicating an antidepressant-like effect. This suggests that mGlu2/3 antagonists might help mitigate depressive-like behaviors in this model.
   • Desipramine (a tricyclic antidepressant) and fluoxetine (a selective serotonin reuptake inhibitor, SSRI) did not show this effect, which might suggest that mGlu2/3 antagonists operate through a different mechanism than conventional antidepressants like SSRIs or tricyclics.
2. Role of AMPA Receptors:
   • The antidepressant-like effect of LY341495 was not blocked by NBQX (an AMPA receptor antagonist), suggesting that the effect of mGlu2/3 antagonists may be independent of AMPA receptor activation. This is important because AMPA receptors are usually involved in synaptic plasticity and glutamate signaling, and their independence from mGlu2/3 antagonists points to a distinct mechanism.
3. Neurochemical Changes:
   • The study observed that chronic corticosterone treatment enhanced the high K+-induced release of dopamine in the prefrontal cortex, but did not affect serotonin or glutamate levels. This neurochemical change was blocked by the mGlu2/3 antagonists (MGS0039 and LY341495), butc not by desipramine or fluoxetine, which suggests that mGlu2/3 antagonists specifically influence dopaminergic release in the prefrontal cortex.
   • Dopamine, which is a key neurotransmitter associated with mood regulation and reward processing, may be playing a critical role in the antidepressant-like effect of mGlu2/3 antagonists.
4. Chronic Corticosterone Model of Treatment-Resistant Depression:
   • The study proposes that chronic corticosterone-treated mice can serve as an animal model for treatment-resistant depression, as the conventional antidepressants (like fluoxetine and desipramine) were ineffective in this model, whereas mGlu2/3 antagonists showed promise.
   • This model may be useful for future studies investigating new treatments for depression, especially for patients who do not respond well to traditional. ⁽¹⁸⁾

"Liraglutide reduces depressive and anxiety-like behaviors in the corticosterone-induced depression model by enhancing hippocampal neural plasticity."

This study investigates the potential of liraglutide, a GLP-1 (glucagon-like peptide-1) analog, as an antidepressant, particularly in the context of chronic stress and depression induced by corticosterone (CORT) in mice. Here's a breakdown of the key findings. ⁽¹⁹⁾

1Liraglutide's Effects on Depressive and Anxiety-like Behaviors:

• Behavioural Studies: Liraglutide administration (at doses of 5 or 20 nmol/kg) significantly attenuated depressive and anxiety-like behaviors in mice subjected to chronic CORT treatment, which is used to model depression.
• Hyperactivity: Liraglutide also reduced the hyperactivity that is typically induced by stress hormones like CORT, indicating that it may help regulate stress-induced changes in behavior. ⁽²⁰⁾

2. Synaptic Plasticity and Hippocampal Effects:

• Synaptic Protection: The study demonstrated that liraglutide treatment protected synaptic plasticity and reversed the suppression of hippocampal long-term potentiation (LTP) induced by CORT. LTP is a process associated with learning and memory, and its suppression is commonly observed in various depression models. This suggests that liraglutide may help restore neuroplasticity, which is often impaired in depression.⁽¹⁹⁾
• Neurogenesis: Liraglutide treatment increased the density of immature neurons in the subgranular dentate gyrus region of the hippocampus. This region is crucial for neurogenesis and emotional regulation, and its enhancement supports liraglutide’s potential antidepressant effects by promoting the growth of new neurons. ⁽¹⁹⁾

"Metabolomic analysis supports the therapeutic potential of gentiopicroside in a corticosterone-induced depression model."

certain plants, on depression. Using corticosterone-induced depression in rats, the research aimed to explore how gentiopicroside might reduce depression-like behaviors and promote neuroprotection by analyzing metabolomic changes. Here's a breakdown of the key findings ⁽²⁰⁾

1. Effect of Gentiopicroside on Depressive Behaviors:

• Corticosterone-induced depression: Corticosterone administration induced depression-like symptoms in rats, including impaired learning and memory, as assessed by the Morris water maze test. This is a well-established test to evaluate spatial learning and memory. ⁽⁹⁾
• Improvement by gentiopicroside: Rats treated with gentiopicroside showed improvements in learning ability, with a reversal of the corticosterone. ⁽²⁰⁾

Thymol alleviates depression-like behaviour and increases hippocampal BDNF levels in the chronic corticosterone-induced depression model in female mice.

The study aims to evaluate the therapeutic effects of thymol in the neurotrophic pathway and its potential as an antidepressant treatment. ⁽¹⁰⁾ Female Swiss mice were divided into four groups: control, corticosterone (Cort), corticosterone with thymol (Cort + Thymol), and corticosterone with fluvoxamine (Cort + Flu). Corticosterone was administered for 23 days to induce depressive symptoms. Behavioral tests (forced swimming, tail suspension, sucrose preference, light/dark, social interaction, Y-maze, plus-maze, and hole-board tests) were conducted to assess the effects. BDNF levels were measured in the hippocampus using ELISA and Western blot analysis. ⁽¹⁰⁾ Both thymol and fluvoxamine reversed depressive symptoms and improved anxiety, anhedonia, and short-term memory. In neurochemical assessments, both treatments restored BDNF levels, alleviating depressive-like behaviour.⁽²⁰⁾

The results suggest that thymol could be a potential therapeutic option for treating depression, warranting further investigation into its clinical applications.⁽²¹⁾

"Metabolomics analysis of corticosterone-induced PC12 cells: A method for assessing an in vitro depression model and uncovering metabolic regulatory mechanisms."

The study demonstrated that poorly-differentiated PC12 cells are the most appropriate in vitro model for studying depression, based on the metabolic alterations they undergo in response to corticosterone. The metabolomics changes observed in these cells were closely aligned with the pathogenesis of depression, making them a relevant tool for investigating the metabolic underpinnings of depression and identifying potential therapeutic targets. ⁽²²⁾Corticosterone induces depressive-like behavior in female peri-pubescent rats, but not in pre-pubescent rats. This study investigates the effects of exogenous corticosterone on depressive-like behavior in juvenile female rats, with a focus on whether the effects differ before and after puberty. The study also explores how corticosterone influences cell proliferation and newborn neuron survival in the hippocampus, a brain region important for mood regulation and neurogenesis.  Here's a breakdown of the key findings: This research demonstrates that corticosterone treatment can induce depressive-like behaviors and impair hippocampal neurogenesis in peri-pubescent (but not pre-pubescent) female rats. The findings highlight that puberty is a critical period during which the brain becomes more sensitive to stress hormones, leading to changes in mood regulation and neurogenesis. The study suggests that the decrease in hippocampal cell proliferation observed in peri-pubescent rats may be a key mechanism underlying the development of depressive-like symptoms. This provides valuable insight into how stress during puberty can contribute to the onset of depression, with potential implications for understanding depression in adolescent females. ⁽²⁴⁾

"Pharmacological evaluation of the depression model induced by repeated corticosterone injections in rats."

This study investigates the pharmacological characteristics of a repeated corticosterone (CORT) injection-induced depression model in rats, with a focus on understanding the mechanisms behind psychotic major depression (PMD). PMD is characterized by psychotic features and is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, particularly elevated cortisol levels. Here's a breakdown of the study and its findings. ⁽²⁵⁾ The study developed and pharmacologically characterized a repeated corticosterone-induced depression model in rats, which mimics psychotic major depression (PMD).⁽²⁶⁾ The model displayed depressive-like behaviors and HPA axis dysfunction, and pharmacological interventions revealed the importance of glucocorticoid receptors and the benefits of combination therapy (antidepressants plus antipsychotics) in treating PMD. This model could be useful for evaluating new treatments targeting the HPA axis and for combination therapies that could be effective for PMD. ⁽²⁷⁾

CONCLUSION:

The studies presented in this article collectively emphasize the pivotal role of corticosterone in mediating depression-like behaviors and its potential as a target for therapeutic interventions. Corticosterone, as a key regulator of stress response, plays a significant role in various models of depression across species, including rodents and birds. The repeated administration of corticosterone results in depressive-like behaviors and neurochemical alterations, particularly through changes in hippocampal BDNF levels, providing a relevant framework for investigating novel antidepressant treatments. Pharmacological agents such as resveratrol, curcumin, metabotropic glutamate receptor antagonists, and liraglutide have shown promising effects in alleviating corticosterone-induced depressive symptoms. These compounds appear to work by restoring neuroplasticity, regulating HPA axis function, and upregulating BDNF expression. Additionally, thymol has been identified as a potential therapeutic alternative, suggesting that further research could unveil its full potential in treating depression. Moreover, studies on the consistency of corticosterone levels in different species, including passerines and reptiles, underscore the role of hormonal plasticity in behavioral and physiological outcomes. This highlights the complexity of hormonal regulation and its implications for evolutionary processes and individual fitness. In conclusion, the corticosterone-induced models of depression provide valuable insights into the pathophysiology of depression and offer a platform for exploring novel therapeutic strategies. Further investigations are needed to fully understand the mechanisms involved and to assess the clinical efficacy of the therapeutic agents discussed, which could ultimately lead to more effective treatments for depression, particularly in cases of HPA axis dysregulation.

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