Elsevier

Steroids

Volume 96, April 2015, Pages 95-102
Steroids

Effect of a novel 5-HT3 receptor antagonist 4i, in corticosterone-induced depression-like behavior and oxidative stress in mice

https://doi.org/10.1016/j.steroids.2015.01.021Get rights and content

Highlights

  • Repeated CORT treatment develops depression-like behavior in mice.

  • 4i, a novel 5HT3 antagonist reverses CORT-induced depression-like behavior.

  • 4i prevents CORT-induced increased brain oxidative insults.

Abstract

Stress in our daily life severely affects the normal physiology of the biological system. Dysregulation of hypothalamic–pituitary–adrenal (HPA) axis has been implicated in the development of depression-like behavior, which remains under diagnosed and poorly treated. Exogenous corticosterone (CORT) administration has been demonstrated to develop a depression model, which has shown to mimic HPA-axis induced depression-like state in rodents. In the present study, the effect of a novel 5HT3 receptor, 4i was examined on CORT induced depression in mice. CORT (30 mg/kg, subcutaneously) was given for 4-weeks to mice in control group, while mice in drug treated group were given 4i (0.5–1 mg/kg, intraperitoneally)/fluoxetine (as a positive control, 10 mg/kg), for the last 2-weeks of CORT dosing. Repeated CORT dosing caused depression-like behavior in mice as indicated by increased despair effects in forced swim test (FST) and anhedonia in sucrose preference test. In addition, CORT administration induced oxidative load in the brain with significant increase in pro-oxidant (lipid peroxidation and nitrite levels) markers and a substantial decline in anti-oxidant defense (catalase and reduced glutathione levels) system, indicating a direct effect of stress hormones in the induction of the brain oxidative damage. On the other hand, 4i and fluoxetine treatment reversed the CORT induced depressive-like deficits. Furthermore, 4i and fluoxetine prevented CORT induced oxidative brain insults, which may plausibly demonstrate one of the key mechanisms for antidepressant-like effects of the compounds. Thus, the study suggests that 5HT3 antagonist; 4i may be implicated as pharmacological intervention targeting depressive-like anomaly associated with HPA-axis dysregulation.

Introduction

Stress is crucially related to the pathophysiology of mood disorders. One of the key adaptive responses to stress involves stimulation of hypothalamic–pituitary–adrenal (HPA) axis releasing glucocorticoids (GCs) (cortisol in humans and corticosterone (CORT) in rodents) to the systemic circulation [1]. GCs elicit a spectrum of physiologic changes that help the organism deal with an acute stressor in an effective manner. However, excessive release of GCs can promote psychological dysfunctions such as depression and anxiety [1], [2]. The hypothesis linking depression and excess GCs is based on the clinical observations that patients with elevated levels of GCs develop depressive-like symptomology and inversely, depressed patients show impairments in HPA axis functions and high circulating GC levels [3], [4], [5]. In addition, earlier studies have shown that high GC levels also correlate with anxiety disorders [6], [7] and more specifically that, depression shows a strong relationship with high levels of GCs when co-morbid anxiety is present [8].

Accordingly, an animal model has been developed using exogenous CORT administration in rodents to mimic the pathophysiological changes associated with stressful events that can invoke depression-like behavior [6], [9]. CORT-induced depression model has advantage over the stress models (such as restraint stress exposure) that it avoid the possibility of potential habituation effects and variation in HPA axis response to stress stimuli [10], [11]. Previous reports have shown that repeated CORT administration develops depression-like behavior in mice during forced swim test (FST) [10]. Chronic treatment with CORT has shown anhedonia-like behavior in sucrose consumption test [12]. Furthermore, preclinical studies have revealed that elevated CORT level is sufficient enough to induce anxiety in mice [6]. David et al. have observed that CORT treated mice exhibit anxiety-like behavior in open field and novelty suppressed feeding paradigms [6]. Therefore, chronic corticosterone treatment appears to model an anxious and depression-like state in mice and help to evaluate the potential activity of compounds in the management of depressive disorders associated with dysfunctional HPA axis activity.

Among the complex interplay of multitudinous pathophysiological factors of depression, oxidative stress has been reported to play a key role [13], [14]. The theory of oxidative stress in depression, at its most basic, can be explained by the concept that excessive amount of free radicals are toxic to the neuronal cells and can affect the physiological activity of the brain [15], [16]. The accumulated reactive oxygen species (ROS) are highly unstable in nature and have potential to damage cellular proteins, lipids and nucleic acids [15]. The endogenous antioxidant enzymes have free radical scavenging action [16]. However, enhanced accumulation of free radicals due to increased production and/or deficiencies of antioxidant defense results in oxidative stress in the brain that culminate in the development of psychological deficits such as depression [13], [17]. Previous reports have shown that repeated CORT treatment results in increased pro-oxidant markers such as lipid peroxidation with subsequent decline in antioxidant enzyme (reduced glutathione and catalase) activities in the brain [18]. This suggests that stress hormones have a causal role in oxidative processes and abnormal activity can have deleterious effects. Furthermore, examining the potential effects of novel compounds on oxidative insults induced by increased GCs activity in correlation with the behavioral response may provide the possible mode of their action and hold important implications for therapeutic interventions.

In the last decade, 5-HT3 receptors have been identified as potential targets for the management of depressive disorders. The antagonism of 5-HT3 receptors has demonstrated antidepressant effects [19]. Unique among the serotonin receptors subtype, 5-HT3 receptors belong to ligand gated ion channels superfamily, which may possibly account for the quick onset of the therapeutic effects (unlike conventional antidepressants, which show recovery of depressive symptomology only after 2–3 weeks of consecutive treatment) and potential activity at lower dose ranges [20], [21], [22], [23], [24]. 5-HT3 receptors antagonists like tropisetron, bemesetron and ondansetron have shown significant antidepressant-like effects in preclinical as well as in clinical studies [19], [20], [24], [25], [26]. Ramamoorthy et al. have shown that ondansetron decreases duration of immobility in FST [20]. When given concomitantly it potentiates the anti-immobility effects of selective serotonin reuptake inhibitors (SSRIs) [27]. Earlier reports have evidenced the antidepressant and anxiolytic-like effects of novel 5-HT3 receptor antagonists (like MCI-225) in rodent behavioral models [28], [29]. Also the recent findings have revealed that novel compounds with potential 5-HT3 antagonistic activity exhibit antidepressant and anxiolytic-like effects [30], [31]. In addition, the findings that the different classes of antidepressants are functional antagonists at 5-HT3 receptors convincingly support the potential activity of 5-HT3 antagonists in attenuating depression-like behavior [32]. In our previous study, we have reported the antidepressant and anti-anxiety-like activity of a novel 5-HT3 receptor antagonist, 4i in acute and chronic rodent models [33]. However, the probable activity of 4i in depression associated with dysfunctional HPA axis activity has not been evaluated. Therefore, the present study was designed to examine the effects of 4i in CORT-induced depression in mice and to clarify the possible involvement of putative 5-HT3 receptors in depression associated with abnormal HPA axis functions. Furthermore, the effects of 4i on oxidative stress in the brain were evaluated as a probable mechanism of action.

Section snippets

Animals

Swiss Albino male mice (22–25 g; age: 11–12 weeks) were obtained from Hisar Agricultural University, Haryana, India. Animals were group housed in cages and were maintained in standard laboratory conditions with alternating light–dark cycle of 12 h each, temperature 23 ± 2 °C and humidity conditions 62 ± 5% relative humidity in the housing unit. Animals had free access to food (standard pellet chow feed) and filtered water ad libitum. Behavioral testing was done during the light cycle. Animals were

Effect of CORT and 4i on spontaneous locomotor activity

The effects of CORT and 4i on the locomotor activity of mice were evaluated and illustrated in Fig. 3. It was found that CORT treatment had no significant effect on the spontaneous locomotor scores [F4,25 = 1.60, p > 0.05] as compared to untreated control mice. Similarly, 4i and FLX (the positive control used in the present study) treatment did not significantly affect the locomotor activity of mice [F4,25 = 1.60, p > 0.05].

Effect of CORT and 4i on forced swim test

As depicted in the Fig. 4, there was a significant increase in the duration of

Discussion

The present study demonstrated the antidepressant-like effects of a novel 5-HT3 receptor antagonist 4i in CORT-induced mouse model of depression (when evaluated in FST and light–dark aversion test) reinforcing that 5-HT3 receptors have an important role in the pathophysiology of depression due to dysregulation of HPA axis. Furthermore, the results showed that 4i has significant attenuating effects on increased oxidative stress in the brain in CORT treated mice revealing the significance of

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Acknowledgments

The authors are thankful to BITS-Pilani and University Grants Commission, India for providing support and research facilities to pursue this work.

References (58)

  • T. Kos et al.

    Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice

    Eur Neuropsychopharmacol

    (2006)
  • G. Bravo et al.

    Acute treatment with 5-HT3 receptor antagonist, tropisetron, reduces immobility in intact female rats exposed to the forced swim test

    Pharmacol Biochem Behav

    (2006)
  • J.P. Redrobe et al.

    Partial role of 5-HT2 and 5-HT3 receptors in the activity of antidepressants in the mouse forced swimming test

    Eur J Pharmacol

    (1997)
  • J. Eguchi et al.

    The anxiolytic-like effect of MCI-225, a selective NA reuptake inhibitor with 5-HT3 receptor antagonism

    Pharmacol Biochem Behav

    (2001)
  • B.K. Gautam et al.

    Antidepressant–like activity of 2-(4-phenylpiperazin-1-yl)-1, 8-naphthyridine-3-carboxylic acid (7a), a 5-HT3 receptor antagonist in behavior based rodent models: evidence for the involvement of serotonergic system

    Pharmacol Biochem Behav

    (2013)
  • T. Devadoss et al.

    Effect of acute and chronic treatment with QCF-3 (4-benzylpiperazin-1-yl)(quinoxalin-2-yl) methanone, a novel 5-HT (3) receptor antagonist, in animal models of depression

    Pharmacol Rep

    (2010)
  • D. Gupta et al.

    Antidepressant and anti-anxiety like effects of 4i (N-(3-chloro-2-methylphenyl) quinoxalin-2-carboxamide), a novel 5-HT3 receptor antagonist in acute and chronic neurobehavioral rodent models

    Eur J Pharmacol

    (2014)
  • J.N. Crawley et al.

    Preliminary report of a simple animal behavior for the anxiolytic effects of benzodiazepines

    Pharmacol Biochem Behav

    (1980)
  • M. Hascoet et al.

    The mouse ligt–dark paradigm: a review

    Prog Neuropsychopharmacol Biol Psychiatry

    (2001)
  • L.C. Green et al.

    Analysis of nitrate, nitrite, and [15 N] nitrate in biological fluids

    Anal Biochem

    (1982)
  • A.K. Sinha

    Colorimetric assay of catalase

    Anal Biochem

    (1972)
  • G.L. Ellman

    Tissue sulfidryl groups

    Arch Biochem Biophys

    (1959)
  • Y. Ago et al.

    Metabotropic glutamate 2/3 receptor antagonists improve behavioral and prefrontal dopaminergic alterations in the chronic corticosterone-induced depression model in mice

    Neuropharmacol

    (2013)
  • B. Lee et al.

    Effects of acupuncture on chronic corticosterone-induced depression-like behavior and expression of neuropeptide Y in the rats

    Neurosci Lett

    (2009)
  • M. Bourin et al.

    The mouse light/dark box test

    Eur J Pharmacol

    (2003)
  • G. Sanacora et al.

    Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders

    Neuropharmacol

    (2012)
  • S. Checkley

    The neuroendocrinology of depression and chronic stress

    Br Med Bull

    (1996)
  • F. Holsboer et al.

    Stress hormone regulation: biological role and translation into therapy

    Annu Rev Psychol

    (2010)
  • S.A. Vreeburg et al.

    Salivary cortisol levels in persons with and without different anxiety disorders

    Psychosom Med

    (2010)
  • Cited by (47)

    • Protective effects of VMY-2-95 on corticosterone-induced injuries in mice and cellular models

      2021, Acta Pharmaceutica Sinica B
      Citation Excerpt :

      Many selective α4β2 nAChR partial agonists such as sazetidine-A19 and nAChRs antagonist such as mecamylamine33 can regulate depression-like behaviors, and researches showed that VMY-2-95 as a selective α4β2 nAChR antagonist could be developed for an antidepressant23. Stress in our daily life severely results in the dysregulation of the HPA axis and then implicates in the development of depression34. It has demonstrated that CORT-mediated hormonal disorders are the direct cause of depressed patients, and exogenous CORT administration could develop mouse depression model mimicking HPA-axis induced depression-like state35,36, leading to depression-like indexes such as reduced sucrose intake and increased immobility time in TST and FST37,38.

    • Is Riparin III a promising drug in the treatment for depression?

      2021, European Journal of Pharmaceutical Sciences
    • A randomized, double-blind, placebo-controlled proof-of-concept study of ondansetron for bipolar and related disorders and alcohol use disorder

      2021, European Neuropsychopharmacology
      Citation Excerpt :

      A study in patients with hepatitis C reported that ondansetron was associated with less fatigue and lower Beck Depression Inventory (BDI) scores than placebo (Piche et al., 2005). In addition, several studies in animal models of depression suggest that ondansetron(Gupta et al., 2014a; Li et al., 2013; Ramamoorthy et al., 2008) and other 5-HT3 antagonists(Gupta et al., 2015, 2014b) may have antidepressant properties. To our knowledge, the current report is the first suggesting improvement in depressive symptoms in people with bipolar disorder given ondansetron.

    • Individual differences in inflammatory and oxidative mechanisms of stress-related mood disorders

      2019, Frontiers in Neuroendocrinology
      Citation Excerpt :

      Moreover, catalase activity has been reported to be increased in depressed patients (Szuster-Ciesielska et al., 2008; Galecki et al., 2009) and decreased in rodents exhibiting depression-like behavior (Gupta et al., 2015; Tsai and Huang, 2016). Lower levels of nonenzymatic antioxidants, such as glutathione, albumin, zinc, uric acid, high-density lipoprotein cholesterol, and coenzyme Q10, as well as lower levels of amino acids such as tryptophan and tyrosine, have been found in the blood of patients with depressive disorders (Maes et al., 2011; Szuster-Ciesielska et al., 2008; Maes et al., 2009; Mico et al., 2011; Rybka et al., 2013; Liu et al., 2015) and in depressed rodents (Gupta et al., 2015). Animal studies have shown that treatment with various antidepressants reduces the intensity of oxidative stress and activates antioxidant enzymes (Eren et al., 2007a, 2007b; Maes et al., 2011; Jiménez-Fernández et al., 2015).

    View all citing articles on Scopus
    View full text