Elsevier

Neuropharmacology

Volume 166, April 2020, 107969
Neuropharmacology

Review article
Therapeutic potential of serotonin 4 receptor for chronic depression and its associated comorbidity in the gut

https://doi.org/10.1016/j.neuropharm.2020.107969Get rights and content

Highlights

  • Expression profile of 5-HT4R in various brain and gut regions.

  • Pharmacological and genomic evidences of 5-HT4R association with depression.

  • Role of 5-HT4R in the brain-gut axis activation and gut function.

  • Expression and function of 5-HT4R in ENS.

  • Clinical significance of potential 5-HT4R agonists and antagonists.

Abstract

The latest estimates from world health organization suggest that more than 450 million people are suffering from depression and other psychiatric conditions. Of these, 50–60% have been reported to have progression of gut diseases. In the last two decades, researchers introduced incipient physiological roles for serotonin (5-HT) receptors (5-HTRs), suggesting their importance as a potential pharmacological target in various psychiatric and gut diseases. A growing body of evidence suggests that 5-HT systems affect the brain-gut axis in depressive patients, which leads to gut comorbidity. Recently, preclinical trials of 5-HT4R agonists and antagonists were promising as antipsychotic and prokinetic agents. In the current review, we address the possible pharmacological role and contribution of 5-HT4R in the pathophysiology of chronic depression and associated gut abnormalities. Physiologically, during depression episodes, centers of the sympathetic and parasympathetic nervous system couple together with neuroendocrine systems to alter the function of hypothalamic-pituitary-adrenal (HPA) axis and enteric nervous system (ENS), which in turn leads to onset of gastrointestinal tract (GIT) disorders. Consecutively, the ENS governs a broad spectrum of physiological activities of gut, such as visceral pain and motility. During the stages of emotional stress, hyperactivity of the HPA axis alters the ENS response to physiological and noxious stimuli. Consecutively, stress-induced flare, swelling, hyperalgesia and altered reflexes in gut eventually lead to GIT disorders. In summary, the current review provides prospective information about the role and mechanism of 5-HT4R-based therapeutics for the treatment of depressive disorder and possible consequences for the gut via brain-gut axis interactions.

This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

Introduction

Views of the recently published WHO report on mental and neurological disorders suggest an alarming prediction, where, one in four people across the world will be affected by mental or neurological disorders at some point in their lives (W.H.O., 2018). At present on a global scale, 450 million people suffer from mental illness. In addition to the suffering, brain dysfunction not only affects mental health but also negatively impacts the vital functions organ systems. In the gut region, severe upset in the physiological or metabolic environment has been reported (Rao and Gershon, 2016, Rao and Gershon, 2017). Anatomically, the gut possesses large pool of enteroendocrine cells and a convoluted intrinsic neural supply for the enteric nervous system (ENS). As an established fact, the gut structure and the involved neurochemistry resembles the structure of central nervous system (CNS), therefore, pathogenic mechanisms that constitutes the CNS disorders possibly lead to ENS dysfunction. Consequently, the nerves those innervate the ENS and CNS could facilitate the spread of disease to other organ systems (Foster and McVey Neufeld, 2013, Mayer et al., 2001). Till date, a cumulative amount of published literature records furnishes an evidence that pathophysiological alterations in ENS function lead comorbidity in GIT. Numerous neurological diseases such as autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson and Alzheimer disease with common pathophysiological mechanisms have initiated comorbidity in GIT (Rao and Gershon, 2016). Most importantly, authors have claimed chronic depression-induced morbidity gains the form of functional gastrointestinal disorder (FGID) such as functional dyspepsia, constipation and irritable bowel syndrome (IBS) (Clark, 1998, Sanger and Quigley, 2010, Wu, 2012). An onset and modulation of psychological problems as well as comorbidity in the gut varies with the amplitude of the causative stressor (e.g. chronic and acute emotional stressors). In fact, chronic depression and anxiety are major risk factors for gut disorders (Zhang et al., 2016). Unfortunately, patients diagnosed with gut disorders coupled with depressive or anxiety condition often suffer severe somatic symptoms, long-lasting recovery, and worst form of prognosis. Interestingly, in accordance to reported literature, the patients of the above-mentioned cases tend to amplify the consumption of medical resources (Mayer et al., 2001). According to an actively involved research groups, the probability of existence for depression and anxiety disorders amongst the patients with digestive system diseases is often high (Haug et al., 2002, Shah et al., 2014). GIT disorders are closely related to anxiety, depression, and other mood disorders, however, associated gut problems cannot be identified for most of the patients that suffer psychiatric diseases. Speaking factually, 40–90% of patients with depressive and anxiety disorders cannot receive proper medication and health care services (Zhang et al., 2016). Likewise, regarding the fact mentioned-above, the mechanisms of depression and its association with GIT disorders poses a major challenge to be resolved in medical sciences. Thus, there is a pressing need to investigate the factors involved in the initiation of psychiatric diseases which may account for the comorbidity in the gut, meanwhile, streamline the path for prevention and treatment of such medical conditions. In the current review, we focus on the pathophysiology of depressive disorders and their consequences on gut function.

Section snippets

Chronic depression: prevalence and aetiology

According to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), depressive disorder has been categorized into bipolar and depressive disorders (APA, 2015). Amongst, chronic depressive disorder and the major depressive disorder (MDD) are two well-known depression types observed in patients (Benazzi, 2006, Culpepper et al., 2015). Although chronic depression also known as dysthymia or persistent depressive disorder (PDD) is the less severe form of depression, it

Mechanism of depression associated pathophysiology of gut

Emotional or physical stress is associated with the “emotional motor system”, which is comprised of the amygdala, hypothalamus, and periaqueductal grey (Conductier et al., 2006, Meneses, 2014g, Reynolds et al., 1995). These brain areas have a descending projection to sympathetic nervous system, parasympathetic nervous system, ENS, and the HPA axis (Fig. 2) (Furness, 2012). During depression, hypothalamic nuclei stimulate the brain stem nuclei (parasympathetic nucleus of vagus) through the

Association of 5-HT system with CNS and gut disorders

Synthesis of 5-HT (Green, 2006, Rapport, 1949, Udenfriend et al., 1955) facilitated the advancements in research for investigating the role of 5-HT in the peripheral and central nervous systems. Subsequently, significant numbers of research papers have been published addressing the various roles of 5-HT in nervous system development, social behavior, and gut function both in vitro and in vivo (Tuladhar et al., 2000, Udenfriend et al., 1955). 5-HT plays an important role in the context of gut

Expression of 5-HT4R in the CNS and gut

5-HT4R is a membrane-bound Gs-protein-coupled receptor (GsPCR) with 3 extracellular loops (ECLs), 7 trans-membrane (TM) helices and 4 intracellular loops including a C-terminal helix (Bockaert and Dumuis, 1998, Padayatti et al., 2013). ECLs contain the N-terminal and a ligand-binding domain which acts as an allosteric regulator site. TM helices contain three important peptide domains at TM2, TM4 and TM7 helices, which control the signal transduction after binding of the ligand to the

Link between 5-HT4R and the depression

In MDD, a decreased expression of 5-HT4R in the striatal region has been observed (Amigo et al., 2016, Madsen et al., 2014). 5-HT4R has an excitatory role on neurons and is widely expressed in limbic regions such as the amygdala, septum, hippocampus and mesolimbic region (Hannon and Hoyer, 2008, Tanaka et al., 2012). 5-HT4R regulates downstream signaling by increasing intracellular cAMP via activation of adenylyl cyclase (Dumuis et al., 1988, Fagni et al., 1992). 5-HT4R has complex variant

Concluding remarks

The 5-HT system is involved in a plethora of physiological functions through the various 5-HTRs. Sustainable emotional and life-threatening stressors induce changes in 5-HT metabolism, neuroendocrine release, and actions of the sympathetic nervous system, parasympathetic nervous system, and ENS. Subsequently, changes induced in neurogenesis, neuronal plasticity, and expression of neurotrophic factors, eventually results in depressive disorder. Because of a similar pathophysiology in CNS, gut

Authors contributions

LA collected the data and drafted the manuscript. MK and SKV helped in the literature survey and manuscript writing. All the authors provided substantial contributions to the discussion of its content and editing. All the graphical illustrations in the manuscript were prepared by LA and SKV.

Declaration of competing interest

Authors declare no competing interest associated with manuscript. All the authors read and approved the final manuscript.

Acknowledgements

We would like to acknowledge Dr. Ronald W. Oppenheim for critically reading the manuscript and Mr. Tarang Mehrotra (Northeastern University, USA) for his valuable suggestions. We also acknowledge Toshimi Otsuka Scholarship Foundation and Grant-in-Aid for Scientific Research (26640024, 17K08487) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan for the support during the study.

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