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

Neuropharmacology 166 (2020) 107969

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Review article

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

T

Lokesh Agrawala,∗∗, Mustafa Korkutatab, Sunil Kumar Vimalc, Manoj Kumar Yadavd,e, Sanjib Bhattacharyyac, Takashi Shigaa,f,∗ a

Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, 305-8577, Tennodai, Tsukuba, Ibaraki, Japan Department of Neurology, Division of Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA c Department of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, PR China d School of Integrative and Global Majors, University of Tsukuba, 1-1-1, 305-8577, Tennodai, Tsukuba, Ibaraki, Japan e Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan f Department of Neurobiology, Faculty of Medicine, University of Tsukuba,1-1-1, Tennodai, Tsukuba, 305-8577, Ibaraki, Japan b

H I GH L IG H T S

profile of 5-HT4R in various brain and gut regions. • Expression and genomic evidences of 5-HT4R association with depression. • Pharmacological of 5-HT4R in the brain-gut axis activation and gut function. • Role and function of 5-HT4R in ENS. • Expression • Clinical significance of potential 5-HT4R agonists and antagonists.

A R T I C LE I N FO

A B S T R A C T

Keywords: 5-HT4R Comorbidity Depressive disorder Gastrointestinal tract HPA axis

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.

1. Introduction

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

Views of the recently published WHO report on mental and

∗

Corresponding author. Department of Neurobiology, Faculty of Medicine, University of Tsukuba 1-1-1 Tennodai, Tsukuba, 305-8577, Japan. Corresponding author. E-mail addresses: [email protected] (L. Agrawal), [email protected] (T. Shiga).

∗∗

https://doi.org/10.1016/j.neuropharm.2020.107969 Received 19 June 2019; Received in revised form 14 January 2020; Accepted 16 January 2020 Available online 20 January 2020 0028-3908/ © 2020 Elsevier Ltd. All rights reserved.

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Abbreviations 5-HT 5-HT4R ACh ACTH AMPA APP CART CGRP CNS CRF ECL ENS FGID GIT

GPCRs HPA IBS MAOI MDD NANC NMDA PVN SNP SERT SSRI TM TPH VIP WHO

5-hydroxytryptamine/Serotonin 5-hydroxytryptamine 4 receptor acetylcholine adrenocorticotropic hormone α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid amyloid precursor protein cocaine- and amphetamine-regulated transcript calcitonin gene-related peptide central nervous system corticotropin-releasing factor extracellular loops enteric nervous system functional gastrointestinal disorders gastrointestinal tract

G-protein coupled receptors hypothalamic-pituitary-adrenal irritable bowel syndrome monoamine oxidase inhibitor major depressive disorder non-adrenergic non-cholinergic N-methyl-D-aspartate paraventricular nucleus single nucleotide polymorphism serotonin transporter selective serotonin reuptake inhibitor trans-membrane tryptophan hydroxylase vasoactive intestinal peptide world health organization

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

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, 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

Fig. 1. Illustrative representation of the stressinduced enduring molecular changes which finally account depressive disorder and affect the physiology of various organ systems. (1) Lifethreatening events induce stress, which leads to the imbalance in the serotonin and glutamate metabolism. (2) These changes in the brain neurotransmitter system affect the expression of neurotrophic factors (BDNF, NT-3, NGF), transcription factors (CREB), protein kinases (mTOR) and the function of voltagegated and ligand-gated ion channels (such as NMDA), (3) which affect the neuronal growth and alter the synaptic circuitry, its function and information processing that finally account for the depressive disorder. (4) Severe/chronic depression leads to significant changes in the neuroendocrine system, neuronal plasticity, gastrointestinal system, metabolic system, and cardiovascular system, hence creating a potential threat for physiologically comorbid diseases in various organ systems including GIT. AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, AKT/PI3K: phosphoinositide 3-kinases, BDNF: brain-derived neurotrophic factor; CRF: corticotropin-releasing factor, FGF: fibroblast growth factor, HPA axis: hypothalamic-pituitary-adrenal axis, mTOR: mammalian target of rapamycin, NGF: nerve growth factor, NT-3: neurotrophin-3, PVN: paraventricular nucleus, VEGF: vascular endothelial growth factor. 2

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serotonin (5-HT) and glutamate, are involved in the advancement of depression (Fig. 1). Malfunction of serotonergic and glutamatergic systems have been reported to induce changes in the expression profile of neurotrophic factors (BDNF, NT-3 and NGF) (Dale et al., 2016; Marazziti, 2017; Švob Štrac et al., 2016), the functions of voltage-gated ion channels α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) following life-threatening events such as physical illness or injury (Mathews et al., 2012). Activation of hypothalamic nuclei also induces secretion of neuroendocrine releasing factors and activates the HPA axis to control various physiological processes of adaptation and maintenance of the body during adverse life conditions (Bao and Swaab, 2019). In addition to the above hypotheses, magnetic resonance scans of human brains have recently found structural ambiguities and significant decrease in the volume of the left hippocampus of MDD patients (Bremner et al., 2000). Bremner et al. claimed that depressive episodes facilitate elevation in glucocorticoid levels and decrease expression of neurotrophins, which could be a cause of hippocampal damage (Bremner et al., 2000). This is one rationale for investigating the role of antidepressants such as selective 5-HT reuptake inhibitors (SSRI) to promote neurogenesis in the hilus and dentate gyrus of the hippocampus, which could be one of the mechanisms behind their actions (Malberg et al., 2000). Stress activates hypothalamic, thalamic, midbrain, pons, and medullary nuclei, which alter various physiological-metabolic processes via cranial-spinal nerve innervation of the digestive system and circulatory system (Gillig and Sanders, 2010; Khazaeipour et al., 2015). Furthermore, these changes in the physiology of the digestive and circulatory systems usually appear as changes such as loss of appetite (Privitera et al., 2013; Simmons et al., 2016), cardiac arrhythmia (Buckley and Shivkumar, 2016), hypertension (Rubio-Guerra et al., 2013), higher body temperature (Rausch et al., 2003), and hypoactive electrodermal response (Sarchiapone et al., 2018). Similarly, depressive patients have been reported to have gastrointestinal problems such as stress-induced flare, swelling, hyperalgesia, and altered reflexes in the gut (Camilleri and Di Lorenzo, 2012; Mayer and Tillisch, 2011; Qin et al., 2014). On the other hand, several reports have pointed out that chronic

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.

2. 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 wellknown 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 increases the risk factors of MDD. MDD is characterized by major episodes or at least two weeks of depressed mood or loss of interest along with four additional symptoms of depression such as sleep disturbance, agitation, and fatigue. Since dysthymia is characterized by at least two years of depressed mood for more days without accompanied by additional depressive symptoms, it does not meet criteria for MDD (APA, 2015). Unlike the MDD, there is little known about effects of dysthymia on the behaviour and physiological conditions (Sansone and Sansone, 2009), although, Major and chronic depression contribute to similar features regarding the adaption of stress and response to pharmacotherapy. Interestingly, several studies indicated that these stress types have different effects on actions of the hypothalamic-pituitary-adrenal (HPA) axis and cytokines released from the HPA axis (Akiskal et al., 1996; Griffiths et al., 2000; Howland and Thase, 1991; Klein et al., 1996). Therefore, it is obvious that dysthymia could persistently account for functional changes in the activity of the HPA axis. Consequently, stress could alter the quality of life, which eventually perpetuates illness to the major depression. The clinical literature has suggested two major postulates based on neurotransmitter system mediating the development of depressive disorder. Researchers proposed that two major neurotransmitters,

Fig. 2. Flow chart explaining the functional role of intrinsic and extrinsic innervation in GIT. During emotional stress, activation of the emotional motor centers in the forebrain limbic regions induces various physiological changes in the body via recruiting the function of the HPA axis and cranial nerve vagus. Activation of the HPA axis induces the release of the adrenal gland hormones, which control the function of GIT. Furthermore, the parasympathetic nucleus of the vagus directly innervates the parasympathetic ganglia and accelerates gut motility. Additionally, limbic forebrain sends the efferent to the spinal cord that further innervates to the sympathetic ganglia via spinal cord preganglionic neurons, which inhibit the GIT motility. HPA axis, sympathetic and parasympathetic nervous system also give chemical and electric signals input to ENS, which is a major intrinsic component of GIT anatomy, thus control the electrolyte secretion, hormonal secretion and peristalsis movement in GIT. ANS: autonomic nervous system, CNS: central nervous system, ENS: enteric nervous system, GI: gastrointestinal, HPA axis: hypothalamic-pituitary-adrenal axis. 3

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system could also modulate the activity of ENS and control gut reflexes through synthesis and secretion of hormones and electrolyte metabolism in the gut (Furness, 2012). Sympathetic innervation to smooth muscles inside GIT reduces gut motility and hormonal secretion contrary to the parasympathetic nervous system, which accelerates motility and endocrine secretion inside the gut (Moloney et al., 2015).

stress might be related to the long-term psychosocial dysfunctions (Yang et al., 2015). The aetiological process of dysthymia relies on the HPA axis and forebrain serotonergic mechanisms (Yohn et al., 2017). However, the effects of other potential factors remain unclear and need further evidence (Griffiths et al., 2000). Usually, the development of dysthymia shows comorbid features in the form of personality disorders or excessive anxiety (Akiskal et al., 1996). Major depression has typically superimposed on a dysthymic state and links to the high rate of disorder repetition (Keller and Shapiro, 1982). Moreover, almost onethird of dysthymic patients also suffer from some comorbid psychiatric and gut disorder (Rao and Gershon, 2016; Weissman et al., 1988), for example, chronic fatigue syndrome patients more likely suffer from constipation and dysthymia (Brunello et al., 1999). Ultimately, chronic depression may also contribute in severe forms of GIT disorders such as functional dyspepsia, gastroparesis, chronic constipation, IBS, stressinduced flare, and visceral hyperalgesia (Rao and Gershon, 2016; Shah et al., 2014; Taylor and Jung, 1998). Recent reports suggest the role of limbic forebrain regions in the pathophysiology of depression and its adverse effect on gut function, but the involvement of specific nuclei or circuit remains unclear.

4. 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 function which is mainly controlled by the autonomic nervous system and the endocrine system (Altaf and Sood, 2008; PazFilho and Mastronardi, 2014; Track, 1980). Inside the gut ENS is an important part of the autonomic nervous system, which has a small neuronal pool of 5-HT and a large pool of 5-HT in enteroendocrine cells (Bulbring et al., 1958; Gershon, 2013). Tryptophan hydroxylase 1 (TPH1) is responsible for 5-HT biosynthesis in this depot (Cote et al., 2003; Walther et al., 2003). In contrast, TPH2 is the rate-limiting enzyme in the biosynthesis of neuronal 5-HT in CNS (Walther et al., 2003). It was previously reported that 5-HT is secreted by enterochromaffin cells into the intestinal mucosa and is involved in the modulation of gastrointestinal function (Bulbring et al., 1958; Gershon, 2013). 5-HT stimulates the mucosal processes of submucosal primary afferent neurons to evoke peristaltic reflexes (Bulbring et al., 1958). However, Bulbring and colleagues could not be certain about the importance of enterochromaffin cells in 5-HT secretion during peristaltic reflex initiation. Later, Boullin performed animal studies and found that peristaltic responses in 5-HT-depleted animals were similar to control animals. Therefore, it was concluded that 5-HT might not be necessary to evoke peristaltic reflexes but could still modulate them (Boullin, 1964). In another study on selective knockouts of TPH1, TPH2, and TPH1 (along with TPH2) confirmed that constitutive gastrointestinal motility depends far more on the small neuronal pool of 5-HT than on the much larger store of 5-HT in enterochromaffin cells (Li et al., 2011). Zhang et al. have argued that single nucleotide polymorphism (SNP) mutation in human TPH2 (hTHP2), a rate-limiting enzyme of neuronal 5-HT synthesis, represents an important risk factor for unipolar major depression (Zhang et al., 2005). Additionally, THP2 has been reported to stimulate enteric neurons and control gut reflexes. Thus, the

3. 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 dorsal longitudinal fascicle and compensate for GIT functioning via the vagus nerve in proportion to the amplitude of the stressor (Browning et al., 2017; Stakenborg et al., 2013). In addition, activation of the hypothalamic paraventricular nucleus (PVN) induces the secretion of corticotropin-releasing factor (CRF) activating the HPA axis, which alters the humoral environment inside the gut. Binding of CRF to its receptors at the anterior pituitary induces secretion of adrenocorticotropic hormone (ACTH), which then activates secretion from the adrenal gland (Herman et al., 2003). In the adrenal cortex and medulla, various neurohormones such as glucocorticoids/cortisol, 5HT, epinephrine, and norepinephrine are secreted to control GIT function via the ENS (Gardner et al., 2019; Smith and Vale, 2006). The limbic system sends direct efferent connections to the spinal cord, and spinal nerves innervate adrenergic and cholinergic neurons in the ganglion of the autonomic nervous system. The autonomic nervous

Fig. 3. Circular tree representation of 5-HTR in CNS and GIT. (A) Expression of the subtypes of 5HTR in the CNS and GIT. (B) Expression of 5-HT4R in the various regions of CNS (Olfactory system, basal ganglia, amygdala, septal regions, hippocampus, hypothalamus, thalamus, cortex, midbrain, pons, medulla, cerebellum, and spinal cord), and GIT.

4

5

Anxiety, Auto receptor, Respiration, Memory, Mood, Sleep, Thermoregulation Yes 5-HT7

Yes

Yes No Yes 5-HT5A 5-HT5B 5-HT6

No No No

Yes Yes 5-HT3 5-HT4

Yes Yes

Yes Yes 5-HT2B 5-HT2C

Yes Yes

Yes Yes Yes Yes 5-HT1D 5-HT1E 5-HT1F 5-HT2A

No No No Yes

Yes 5-HT1B

No

Auto receptor, Locomotion, Sleep Functions in rodents, Pseudogenes in human Anxiety, Cognition, Learning, Memory, Mood

(Lummis, 2012; Meneses, 2014f; Thompson and Lummis, 2006) (Bockaert et al., 2008; Bureau et al., 2010; Hagena and ManahanVaughan, 2017; Kozono et al., 2017; Meneses, 2014g) (Gonzalez et al., 2013; Meneses, 2014h; Thomas, 2006) (Grailhe et al., 2001; Meneses, 2014h) (Geng et al., 2018; Meneses, 2014i; Ramírez, 2013; Woods et al., 2012) (Ciranna and Catania, 2014; Hedlund, 2009; Meneses, 2014a; j; Nikiforuk, 2015)

(De Vries et al., 1999; Pullar et al., 2004; Skingle et al., 1996) (Klein and Teitler, 2012; Meneses, 2014d) (Meneses, 2014d; Ramadan et al., 2003) (Guiard and Giovanni, 2015; Meneses, 2014e; Raote et al., 2007)

(Clark and Neumaier, 2001; Meneses, 2014c)

(Garcia-Garcia et al., 2014; Meneses, 2014b) Yes 5-HT1A

Expression in GITract Expression in CNS Type of 5-HTR

Table 1 Expression and function of 5-HT receptors in CNS and gut.

Function

Emotional, physical and other stressors in the external environment are the main cause of depression. Persistence of the stress for a prolonged period could lead to significant changes in neurotransmitters, neuroendocrine systems and disturb neural circuitry and eventually cause depressive disorder. In fact, depression is a biochemically heterogeneous process by nature (Fig. 1). Animal studies showed that stressors cause changes in the release of 5-HT, norepinephrine, and dopamine (Anisman et al., 1992; Maas, 1975). Additionally, relations between 5-HT2 receptors, dopamine auto-receptors, and α1-adrenergic or β-adrenergic receptors are well known in depression (Antelman et al., 1995; Brown and Gershon, 1993; Coppen et al., 1972; Crowell, 2004; Jimerson, 1987; Siever, 1987; Meltzer, 1989; Sulser, 1984; Van Praag, 1978). Recent treatment strategies for depression have received considerable attention and led researchers to mainly focus on 5-HTRs and dopamine receptors-based medications (Belujon and Grace, 2017; Nautiyal and Hen, 2017; Yohn et al., 2017). In this review, we explain in some detail the potential role of 5-HT4R in chronic depression and its associated comorbidity in the gut. Briefly, it is well known that functions of all the 14 subtypes of 5HTR are controlled by the synthesis and availability of 5-HT. Among them, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, and 5-HT7 receptors are dominantly expressed in both CNS and gut (Fig. 3A). At the beginning of the 1950s pharmaceutical companies introduced drugs, known as monoamine oxidase inhibitors (MAOIs), which inhibit MAO to control the bioavailability of 5-HT, norepinephrine, epinephrine and dopamine (Yohn et al., 2017). MAOIs were the first efficient antidepressant drugs which increase the extracellular levels of 5-HT and elevate mood in depressive patients (Artigas et al., 1996; Bel and Artigas, 1999; Ross and Renyi, 1969; Tatsumi et al., 1997). However, due to various side effects of MAOIs, new drugs called tricyclics were synthesized and were subsequently developed for the treatment of depression, although the problems remained the same (Gillman, 2007). Later, second-generation antidepressants such as selective SSRIs were developed and showed a significant effect with an improved profile of safety and fewer side effects (Hillhouse and Porter, 2015). Interestingly, SSRIs inhibit 5-HT re-uptake into 5-HT neurons and increase 5-HT levels throughout the brain. The success of SSRIs for chronic depression treatment has led researchers to explore 5-HTRs as a potential therapeutic for the cure of psychiatric problems including chronic depression and anxiety (Hieronymus et al., 2018). There is a growing number of reports indicating the pharmacological importance of the 5-HTR subtypes 5-HT1A, 5-HT1B, 5-HT2, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 in rodent models of anxiety and depression (Table 1) (Chagraoui et al., 2019; Ciranna and Catania, 2014; Clark and Neumaier, 2001; Di Giovanni and De Deurwaerdère, 2016; Diaz et al., 2012; Garcia-Garcia et al., 2014; Geng et al., 2018; Grailhe et al., 2001; Guiard and Giovanni, 2015; Hedlund, 2009; Klein and Teitler, 2012; Nikiforuk, 2015; Richardson-Jones et al., 2010; Thomas, 2006).

Addiction, Auto receptor, Aggression, Anxiety, Sleep, Appetite, Sexual behavior, Mood, Memory, Nausea, Nociception, Sociability, Thermoregulation, Vasocontraction Addiction, Auto receptor, Aggression, Anxiety, Sexual Behavior, Mood, Memory, Learning, Locomotion, Penile erection Anxiety, Auto receptor, Locomotion Memory Migraine Addiction, Anxiety, Appetite, Cognition, Imagination, Learning, Memory, Perception, Sleep, Thermoregulation, Sexual behavior Anxiety, Appetite, Cardiovascular function, Sleep, Vasodilation, Gastrointestinal motility Anxiety, Appetite, cardiovascular function, Sleep, Vasocontraction, Gastrointestinal motility, Thermoregulation, Sexual behavior, Mood, Locomotion, Penile erection, Locomotion Addiction, Anxiety, Appetite, Learning, Memory, Gastrointestinal motility, Nausea Anxiety, Depression, Appetite, Learning, Memory, Gastrointestinal motility, Mood, Respiration

References

4.1. 5-HTR and depressive disorder

No

aforementioned studies suggest human genetic correlations for depression and gastrointestinal dysfunction (Walther et al., 2003; Zhang et al., 2005). More recently, a study in knock-in mice (TPH2-R439H) confirmed the role of neuronal 5-HT in depression and associated comorbidity in the gut, where levels of 5-HT were significantly lower in enteric neurons (Israelyan et al., 2019). TPH2-R439H mice had a lower level of 5-HT in enteric neurons which caused abnormalities in ENS development and led to ENS-mediated gut dysfunctions like reduced motility and growth of intestinal epithelium. Total GI transit time and propulsive colorectal motility were slower in TPH2-R439H mice than control, which demonstrates the importance of 5-HT as a link between brain and gut axis.

(Diaz et al., 2012; Meneses, 2014e) (Canal and Murnane, 2017; Meneses, 2014e)

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the C-terminus of human 5-HT4R has 10 splice variants a, b, c, long c, d, e, f, g, i, and n (Table 2), which differ in their C-termini after a single position (L358) (Blondel et al., 1998; Bockaert et al., 2004; Brattelid et al., 2004; Coupar et al., 2007; Ray et al., 2009) . 5-HT4R is widely expressed both in CNS and gut (Fig. 3B) (Bockaert and Dumuis, 1998; Hegde and Eglen, 1996; Reynolds et al., 1995). Except for isoform (d), human 5-HT4R isoforms (a–i and n) are highly expressed in the CNS (Blondel et al., 1998; Bockaert et al., 2004; Vilaró et al., 2002). Of these, isoform (b) is the most abundant form in the CNS and periphery and is expressed in the caudate nucleus, putamen, amygdala, pituitary gland, and small intestine. In contrast, isoform (a) is highly expressed in the amygdala, hippocampus, nucleus accumbens, and caudate nucleus and at lower levels in the small intestine, atrium, and pituitary gland. Isoform (c) is highly expressed in the pituitary gland and small intestine and to a lesser extent in the caudate nucleus, hippocampus, and putamen, whereas isoform (d) is the only variant of 5-HT4R, which is not present in the CNS but is found in the small intestine (Bockaert et al., 2004; Vilaró et al., 2002, 2005). Interestingly, isoform (g) seems to be highly expressed in the hypothalamus and cortex (Claeysen et al., 1998) and isoform (n), which lacks the alternatively spliced C-terminal exon is abundantly expressed in peripheral tissues and brain regions involved in mood disorders (frontal cortex and hippocampus) (Vilaró et al., 2002). Hence, the selective therapeutic use of a particular variant of 5-HT4R in specific brain and gut regions may increase the specificity and effectiveness of treatments.

4.2. Considerable evidence supports the role of 5-HTR genes in depression and its comorbidity in the gut Recent studies on animal models of depression have suggested that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in psychiatric diseases (Haug et al., 2002; Mayer et al., 2001; Shah et al., 2014; Zhang et al., 2016). Although there is a strong epidemiological association between depression and gut diseases, there is no direct relationship yet observed. However, there may be common genetic predispositions particularly in the genes that are involved in 5-HT signalling (Rao and Gershon, 2016). In this context, TPH2 gene knockout studies suggest that the synthesis of 5-HT in a small pool of enteric neurons is a major factor mediating gut reflexes. Zhang et al. have proposed that SNP mutation in human TPH2 (hTHP2) represents an important risk factor for unipolar major depression (Zhang et al., 2005), which suggests that 5-HT may induce comorbidity in the brain and gut. It has also been reported that homozygous G-protein beta-3 C825T polymorphism, coupled with 5HTR, is associated with functional dyspepsia and depression in mammals (Holtmann et al., 2004). Another study showed that SNP of 5-HT transporter (SERT) genes is associated with the subtypes of IBS (Pata et al., 2002). Recently, Wohlfarth et al. reported that SNP in 5-HT3AR (C178T; rs1062613) and 5-HT4R (rs201253747) genes are associated with increased anxiety and amygdala responsiveness as well as in the severity of IBS symptoms (Wohlfarth et al., 2017). Furthermore, SNP in 5-HT4R genes affects the binding of miR-16 and miR-103/miR-107 mRNAs and impairs the function of 5-HT4R, which was downregulated in IBS-D patients (Wohlfarth et al., 2017).

5.2. Role of 5-HT4R in the brain and gut Clearly, during development, 5-HT4R is highly expressed in the limbic region of the brain and plays an important role in information processing and memory formation in the hippocampus (Hagena and Manahan-Vaughan, 2017; Teixeira et al., 2018). Recently, our group showed a role for 5-HT4R in embryonic rodent brain development (Agrawal et al., 2019; Kozono et al., 2017); treatment of 5-HT4R agonists RS67333, BIMU8, and 5-HT itself increased the expression of neurotrophic factors (BDNF, NT-3, NGF), TRK-A and CRMP2 in the hippocampus and promoted the growth of axons and dendrites (Agrawal et al., 2019). Additionally, our preliminary data from an extended study on mice pups has shown that oral administration of RS67333 during early postnatal weeks decreases anhedonia-like behavior and increases BDNF expression in the adult hippocampus. Further, in adult brain, pharmacological intervention with 5-HT4R had a critical role in anxiety and depression in rodents via increasing the expression of neurotrophic factors, TRK-B, phosphorylated CREB, Arc, and 5HT1AR (Amigo et al., 2016; Kennett et al., 1997; Lucas et al., 2007; Yohn et al., 2017). Lucas et al. reported a rapid antidepressant effect of agonist RS67333 (Lucas et al., 2007), whereas Kennett et al. showed an anxiolytic effect of antagonists SB204070A and SB207266A in rats (Kennett et al., 1997). Recent studies report that various 5-HT4R agonists improve cognition and memory function in rodents by stimulating the release of acetylcholine (ACh) (Consolo et al., 1994). Consolo and

5. Expression and functions of 5-HT4R in the CNS and gut 5.1. 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 ligandbinding 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 extracellular ligand-binding domain (Padayatti et al., 2013). Ligand binding to the receptor-binding pocket decreases oxidation rates at the specific peptide domains in TM helices and increases the oxidation rates at the C-terminus domain and facilitates intracellular interactions (Padayatti et al., 2013). C-terminal of 5-HT4R contains specific PDZ ligands (Joubert et al., 2004), which enable the interaction between C-termini of 5-HT4R to various PDZ domain-containing GPCRinteracting proteins. Human htr4 gene encompassing 38 exons spanning over 700 kb, therefore, multiple C-terminal isoforms are expressed in specific tissues (Bockaert et al., 2004; Coupar et al., 2007; Rebholz et al., 2018). There are 11 human 5-HT4R splice variants. Among them, Table 2 C-terminal splice variants of 5-HT4R in CNS and gut. 5–HT4R splice variant

Variance in the C-terminal sequence

Tissue

a b c long c d e f g i

STTTINGSTHVLRYTVLHRGHHQELEKLPIHNDPESLESCF STTTINGSTHVLRDAVECGGQWESQCHPPATSPLVAAQPSDT STTTINGSTHVLSSGTETDRRNFGIRKRRLTKPS STTTINGSTHVLSSGTETDRKKLWNKEEKIDQTIQMPKRKRKKKASLSYEDLILLGRKSCFREGK STTTINGSTHVLRF STTTINGSTHVLSFPLLFCNRPVPV STTTINGSTHVLSPVPV STTTINGSTHVLSGCSPVSSFLLLFCNRPVPV STTTINGSTHVLRTDFLFDRDILARYWTKPARAGPFSGTLSIRCLTARKPVLGDAVECGGQWESQCHPP ATSPLVAAQPSDT STTTINGSTHVLR

CNS, Esophagus, Stomach, Ileum, Colon CNS, Esophagus, Stomach, Ileum, Colon CNS, Ileum CNS, Stomach, Colon Ileum, Colon CNS, Ileum, Colon CNS, Ileum, Colon CNS, Ileum, Colon CNS, Ileum, Colon

n

6

CNS, Esophagus

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and subjectively improved stool evacuation and shortened total colonic transit time (P < 0.05) (Liu et al., 2005). Clinical evidences based on a study of 500 Japanese participants showed that following 4 weeks of treatment with mosapride significant relief was observed in the upper GI symptoms in participants (Sakurai et al., 2012; Stanghellini, 1999). Combination therapy with probiotics and mosapride is effective for the relief of symptoms in patients with non-diarrheal-type IBS (Choi et al., 2015). A later study by Coremans et al. suggests its use in the treatment of chronic constipation in IBS patients (Coremans, 2008). Later, Alphin et al. showed the antiemetic activity, gastric motor activity, and antidopamine receptor effects of the new synthesized 5-HT4R drugs metoclopramide and dazopride in dogs (Alphin et al., 1986). Currently, metoclopramide is the only US FDA-approved medication for the treatment of gastroparesis (Lee and Kuo, 2010; Snape et al., 1982). Further, Alarcon et al. reported the role of cinitapride as a gastroprokinetic agent (Portincasa et al., 2009) and antiulcer agent (Alarcon de la Lastra et al., 1998). Research by Beecham pharmaceuticals indicates that renzapride (BRL24924), a molecule originally identified as a potent stimulant of gastric motility without the ability to antagonize at the D2 receptor (Miner et al., 1986, 1987; Sanger, 1987), promoted this drug as a novel prokinetic agent in diabetic gastroparesis (Mackie et al., 1991). Therefore, based on these data, we can conclude that 5HT4R is functionally expressed both in the brain and gut. Therefore, 5HT4R has become an important focus of research in searching for alternative solutions for the treatment of common neuropsychological and gut problems (Bockaert et al., 2008; Sanger and Quigley, 2010) (see Table 3).

colleagues reported a stimulatory effect of BIMU8 on ACh release in the frontal cortex (Consolo et al., 1994). Later, Siniscalchi and colleagues reported that BIMU8 increased the outflow of ACh in the hippocampus and enhanced memory and cognition, which were blocked by concomitant treatment with a 5-HT4R antagonist GR125487 (Siniscalchi et al., 1999). There are some reports showing that the stimulatory role of 5-HT4R agonists VRX-03011 (Mohler et al., 2007) and RS67333 in memory and learning could be reversed with treatment of antagonists SDZ 205–557 and GR125487 (Fontana et al., 1997; Meneses and Hong, 1997; Orsetti et al., 2003). In contrast, other groups reported that the expression level of 5-HT4R was inversely associated with memory recall in humans (Haahr et al., 2013; Stenbæk et al., 2017). A recent study reported that deposition of neurofibrillary tangles and amyloid precursor protein (APP) were cleared and Alzheimer disease patients showed significant improvements in motor activities when treated with 5-HT4R-based therapeutics (Coskuner-Weber and Uversky, 2018). 5HT4R drives APP processing towards a beneficial non-amyloidogenic pathway via direct interaction with α-secretase ADAM10 or β-secretase BACE1 and leads to the breakdown of APP into soluble APP without any toxic effects (Baranger et al., 2017; Cochet et al., 2013; Giannoni et al., 2013; Lalut et al., 2017). 5-HT4R can also regulate tau pathology by modulating the activity of GSK-3β via G12/13 proteins (Butzlaff and Ponimaskin, 2016). In addition to the CNS, 5-HT4R also plays an important role in gut function. The gut contains a large pool of 5-HT4R in enterochromaffin cells and a smaller pool in enteric neurons (Hegde and Eglen, 1996; Liu et al., 2009; Rao and Gershon, 2017). During development, 5-HT neurons in the gut appear in early prenatal stages and affect the survival of later-born dopaminergic, gamma-aminobutyric acidergic, nitrergic, and calcitonin gene-related peptide-expressing neurons which are essential for gastrointestinal motility (Li et al., 2011; Takaki et al., 2014). A study on 5-HT4R knockout mice suggested its role in enteric neuron survival and/or neurogenesis, which supports its role in ENS growth and maintenance (Liu et al., 2009). Veysey and colleagues reported the role of a 5-HT4R agonist cisapride on gall bladder emptying, intestinal transit, and mucosal healing. It also stimulates motor activity in all segments of the GIT by enhancing the release of ACh from the ENS (Tack et al., 1995; Veysey et al., 2001). In clinical trials, cisapride demonstrated benefit in both short- and long-term therapy of gastroparesis and dyspepsia (Abell et al., 1991; Camilleri et al., 1989; Quigley, 2015). Subsequently, withdrawal of cisapride led to interest in the development of alternative 5-HT4 agonists that led to the discovery of tegaserod. This drug has been reported to accelerate intestinal transit (Prather et al., 2000), reduce esophageal acid exposure (Kahrilas et al., 2000), and promote gastric accommodation (Tack et al., 2003). Therefore, tegaserod was approved for the management of constipation-predominant IBS, but side effects on cardiovascular system resulted in its ultimate withdrawal (Busti et al., 2004). After a gap of some years, interest was renewed for 5-HT4R agonists, which led to the development of prucalopride. This drug is now available in several countries. In contrast to cisapride and tegaserod, prucalopride (a benzofuran) is a highly selective 5-HT4R agonist that has a high affinity for 5-HT4R and has very low affinity for other 5-HTRs (Quigley, 2012). Prucalopride has been examined in three large (> 500 patients), multicenter, double-blind, placebo-controlled trials; the results indicate that prucalopride significantly improved bowel function, reduced constipation-related symptoms and improved patient satisfaction (Camilleri et al., 2008; Quigley et al., 2009; Sanger and Quigley, 2010; Tack et al., 2009). Furthermore, mosapride was synthesized, a benzamide derivative that acts as a selective 5-HT4R agonist in the GIT, and does not appear to have any significant affinity for 5-HT1, 5-HT2, dopamine D2, or adrenergic (alpha 1 or alpha 2) receptors (Yoshida et al., 2011). Mosapride is available as a prokinetic agent in several Asian countries and is being used for the treatment of functional dyspepsia (Hallerback et al., 2002). In addition, mosapride administration (15 mg/day) to patients with Parkinson disease objectively improved stool frequency

6. Depression induced comorbidity in gut and its association with 5-HT4R 6.1. 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 C-terminal due to alternative splicing of the mRNA. It was reported that SNPs in C-terminus of 5-HT4R at IVS1+15 T/C, IVS3+6 G/A, IVS3–63C/T, IVS4−36 T/C, g.83097C/T, g.83159G/A, g.83164(T)9–10, and g.83198A/G, were observed in schizophrenia and in depressive disorders in a Japanese population (Ohtsuki et al., 2002). In addition, several studies have found that depressed violent suicide victims have differential patterns of 5-HT4R binding and cAMP concentration levels in different brain regions (Rosel et al., 2004). Recently 5-HT4R-based drugs such as the selective partial agonist RS67333 have shown a rapid onset of action during treatment of chronic depression in rodent animal models (Lucas et al., 2007). 6.2. Pathophysiology of the HPA axis in depression-induced comorbidity in gut and the role of 5-HT4R Serotonergic systems are known to modulate activity in the HPA axis (Smith and Vale, 2006). Accordingly, it is somewhat surprising that only the raphe nucleus sends direct serotonergic innervation to PVN neurons (Herman et al., 2003; Laflamme et al., 1999). It was reported that pharmacological depletion of 5-HT inhibited c-fos induction and CRF heteronuclear RNA expression in the PVN (Harbuz et al., 1996; Laflamme et al., 1999). Lesion studies lend further support for a stimulatory role of 5-HT in HPA axis regulation. Electrolytic or neurochemical lesions of the raphe nuclei elicit decreased HPA responses to restraint stress, photic stimuli, and local PVN glutamate administration (Feldman and Weidenfeld, 1997). Stimulation of the dorsal 7

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Table 3 Potential agonists and antagonists of 5-HT4R and their therapeutic role. Name (Chem Id)

Type

Application in medical/research and reference

Structure

Cumulative evidences in animal models and human subjects

5-HT-HCl (140983)

Endogenous agonist

Mood disorders (Ansorge et al., 2004), Gut reflexes (Bulbring et al., 1958; Hoffman et al., 2012)

5-HT altered the emotional behavior in mice (Ansorge et al.), and initiated the reflexes in intestine of guineapigs (Bulbring et al.; Hoffman et al.).

BIMU8 (4470566)

Selective agonist

Respiratory depression (Manzke et al., 2003) Brain development (Agrawal et al., 2019; Kozono et al., 2017) Nootropic (Consolo et al., 1994) Abdominal nociception (Lyubashina et al., 2016)

BIMU8 reestablished the opioid induced breathing depression in rats (Manzke et al.), promoted the developmental of hippocampal neurons in mice and rats (Agrawal et al.; Kozono et al.), and suppressed abdominal nociception in rats (Lyubashina et al.).

RS-67333 (159808)

Partial selective agonist (Hydrophobic)

Rapid anxiolytic and antidepressant (Lucas et al., 2007; Mendez-David et al., 2014) Alzheimer's disease (Giannoni et al., 2013) Memory and learning (Fontana et al., 1997; Meneses and Hong, 1997; Orsetti et al., 2003)

RS-67333 showed rapid antidepressant and anxiolytic effect in rats and mice (Lucas et al.; Mendez-David et al.), prevented amyloid genesis and behavioral deficits in the mice (Giannoni et al.), and showed antiemetic effects in rodents (Fontana et al.; Orsetti et al. and Menesses et al.)

RS-17017 (7974774)

Agonist (Hydrophilic)

Learning and memory (Terry et al., 1998).

RS-17017 improved the delayed matching performance in old and young macaque monkeys, which signifies its role in Alzheimer's and memory disorder (Terry Jr et al.).

Cisapride (5292927)

Agonist

Gastroprokinetic agent (Tack et al., 1995; Veysey et al., 2001).

Dazopride (49487)

Agonist

Gastroprokinetic agent (parasympathomimetic) (Alphin et al., 1986)

Cisapride induced gall bladder emptying, intestinal transit, mucosal healing and stimulated motor activity in all segments of the gastrointestinal tract by enhancing the release of acetylcholine from the enteric nervous system in the human subjects (Veysey et al.) Alphine et al. showed the antiemetic activity, gastric motor activity, and antidopamine receptor effects of dazopride in dogs.

Metoclopramide Hydrochloride (22122)

Agonist

Gastroprokinetic (Alphin et al., 1986) Gastroparesis in patients with diabetes (Snape et al., 1982)

Metoclopramide is US FDAapproved medication for the treatment of gastroparesis

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Table 3 (continued) Name (Chem Id)

Type

Application in medical/research and reference

Structure

Cumulative evidences in animal models and human subjects (Lee and Kuo; Snape et al.), and reported to affect antiemetic activity, gastric motor activity, and antidopamine receptor effects in dogs (Alphin et al.).

Mosapride citrate (MOS)/M1 (106779)

Selective agonist

Gastritis, Gastroesophageal reflux disease (Sakurai et al., 2012) Functional dyspepsia (Bang et al., 2015) Irritable bowel syndrome (Choi et al., 2015).

In humans, combination therapy with probiotics and mosapride is effective for relief of symptoms in patients with non-diarrheal type IBS (Choi et al.).

Prucalopride (2314539)

Selective, high affinity agonist

Chronic constipation, Normalizing bowel movements (Coremans, 2008).

Coremans et al. reported use of prucalopride in the treatment of chronic constipation in IBS patients.

Cinitapride (62099)

Agonist

Gastroprokinetic agent (Portincasa et al., 2009) Antiulcer agent (Alarcon de la Lastra et al., 1998)

Renzapride (16736758)

Full agonist

Gastroprokinetic agent (Sanger, 1987), Antiemetic (Miner et al., 1986, 1987) Diabetic gastroparesis (Mackie et al., 1991)

Tegaserod (10609889)

Agonist

Irritable bowel syndrome and constipation (Kahrilas et al., 2000; *Prather et al., 2000; Srivijaya et al., 2008; Tack et al., 2003)

Cinitapride decreased the transit time for patients with mild-to-moderate delayed gastric emptying (Portincasa et al.), gastroprotective effect through reduction of neutrophil toxicity and by an increased synthesis of freeradical scavenging enzymes glutathione peroxidase in rats (Alarcon de la Lastra et al.). Renzapride (BRL24924) identified as a potent stimulant of gastric motility without ability to antagonize the D2 receptor in ferrets/ domesticated polecat (Miner et al., 1986, 1987; Sanger, 1987) and for the treatment of gastroparesis in diabetic patients (Mackie et al.). Tegaserod showed an ability to accelerate intestinal transit, reduce esophageal acid exposure, and promoted gastric accommodation and was FDA approved for the management of constipationpredominant IBS patients.

Zacopride (97262)

Agonist

Anxiolytic (Costall et al., 1988), Antiemetic (Smith et al., 1989), Sleep apnea (Carley et al., 2001), Respiratory depression (Meyer et al., 2006), Aldosterone secretion (Lefebvre et al., 1993)

L-lysine

Partial Antagonist

Anxiety (Smriga et al., 2007), Diarrhea, Ileum contractions,

(5747)

Zacopride showed anxiolytic effect in rodents and primate models of anxiety (Costall et al.), emetogenic effect in dogs (Smith et al.), reduced sleep apnea in rats (Carley et al.), reversed opioidinduced respiratory depression and hypoxia in goats (Meyer et al.), and stimulated aldosterone release in human adrenocortical tissue in vitro (Lefebvre et al.). L-lysine was reported to normalize hormonal stress

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Table 3 (continued) Name (Chem Id)

Type

Application in medical/research and reference

Structure

Tachycardia and in stress-induced fecal excretion (Smriga and Torii, 2003)

Cumulative evidences in animal models and human subjects responses in humans with high trait anxiety, blocked stress-induced fecal excretion, reduced the severity of diarrhea, and affect cardiovascular responses in rat and ileum contractions in guinea pig (Smigra et al.) Piboserod induced delayed colonic transit times in IBS-D patients (Bharucha et al. and Hammerle et al.) and reduced left ventricular function in patients with symptomatic heart failure (Kjekshus et al.).

Piboserod (SB207266) (154413)

Antagonist

Atrial fibrillation (Kjekshus et al., 2009) Irritable bowel syndrome-D (Bharucha et al., 2000; Hammerle and Surawicz, 2008)

GR-125487 (3491209)

Selective antagonist

Anti-gastroprokinetic agent (Choi et al., 2017)

GR-125487 blocked the prokinetic effect in rat model of delayed GIT and inhibited the 5-HT4R induced gut reflexes (Choi et al.).

GR-113808 (106623)

Selective antagonist

Anti-gastroprokinetic agent (Gale et al., 1994)

GR-113808 blocked the prokinetic effect of 5-HT4R agonist in the guinea pig isolated ascending colon and rat isolated esophagus and showed its importance in IBSD (Gale et al.).

NS-3389

Antagonist

Antiemetic effects (Minami et al., 1997)

N-3389 showed antiemetic effects in ferrets by inhibition of 5-HT3 and 5-HT4 receptors on the abdominal afferent vagus nerves (Minami et al.).

SB-204070 (108731)

Selective antagonist

Anti-gastroprokinetic agent (Tuladhar et al., 2003)

SB-204070 restored the inhibitory effect of 5-HT on peristalsis in the guinea-pig ileum (Tuladhar et al.).

SB-203186 (2521721)

Antagonist

Tachycardia (Kaumann et al., 1993) Gastric motility (Komada and Yano, 2007)

SB-203186 restored the 5-HTevoked tachycardia in piglet sinoatrial (Kaumann et al.), and enhanced contractions in antrum and fundus (Komada and Yano).

SB-205800 (8375381)

Antagonist

Atrial fibrillation, Irritable bowel syndrome, Stroke and CNS disorders (Gaster and King, 1997; LopezRodriguez et al., 2002)

SB-205800 is at the preclinical stage of development for the treatment of atrial

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Table 3 (continued) Name (Chem Id)

Type

Application in medical/research and reference

Structure

Cumulative evidences in animal models and human subjects fibrillation, IBS, stroke and CNS disorders.

SDZ-205557 (5003)

Selective and surmountable antagonist

Anti-gastroprokinetic (Eglen et al., 1993)

SDZ-205,557 antagonized 5HT4-mediated stimulation of adenylyl cyclase in guinea-pig hippocampus and carbacholcontracted esophagus in rats.

SC-53606 (118156)

Selective antagonist

Anti-gastroprokinetic agent (Becker et al., 2006; Yang et al., 1993)

SC-53606 induced relaxation of carbachol-induced contractions in rat esophageal tunica muscular mucosae.

AID-707291

Antagonist

Analgesic action (Furlotti et al., 2012)

AID-707291 showed antinociceptive effect in mice models as a 5-HT4R antagonist with analgesic action.

(Source of chemical structures: http://www.chemspider.com/).

intracerebroventricular injection of CART peptide resulted in neuronal activation in CRF neurons in the PVN for regulating the HPA axis (Stanley et al., 2001). Additionally, the fact that PVN neurons can be excited/inhibited directly by 5-HT4R agonist/antagonist (Ho et al., 2007), supports the idea that serotonergic stimulation to 5-HT4R in PVN may increase CART mRNA levels and facilitate the secretion of CRF, which further activates the HPA axis via stimulating ACTH from the anterior pituitary gland (Lau and Herzog, 2014; Stanley et al., 2001). Recent findings suggest that 5-HT signaling in multiple regions of the brain and spinal cord can potentially modulate central drive to the peripheral sympathetic nervous system, which alters endocrine secretion from the adrenal gland (Brindley et al., 2017). The overall effect varies depending on the neuronal pathways recruited by the stressor and the serotonergic innervation and receptor expression in those respective pathways (Brindley et al., 2017; Tjurmina et al., 2002). Loss of SERT function enhances the increases in plasma epinephrine, but not norepinephrine, evoked by restraint stress or hypoglycemia (Sanders et al., 2008). Alternatively, SERT could act locally within the adrenal

hippocampus or the central amygdaloid nucleus also indicates that the effects of 5-HT may be exerted directly in the PVN and/or in surrounding regions (Feldman et al., 1987; Feldman and Weidenfeld, 1998). Notably, 5-HT heavily innervates forebrain stress-integrative structures, including the hippocampus, prefrontal cortex, amygdala, and hypothalamus (Lowry, 2002). Thus, in addition to direct actions at the PVN, systemic or intracerebroventricular injections of serotonergic drugs may also influence HPA activity indirectly (Feldman and Weidenfeld, 1998). Although many studies indicate that 5-HT stimulates ACTH and corticosterone secretion by the activation of 5-HT2A and 5-HT1A receptors on CRF neurons in the PVN (Pan and Gilbert, 1992; Van de Kar et al., 2001), the role of 5-HT4R in the activation of HPA axis cannot be ignored. Herman et al. reported that central 5-HT4R exerts an excitatory regulation on rat dorsal raphe nucleus which is the only serotonergic supply to CRF neurons in the PVN (Herman et al., 2003). Jean et al. reported that 5-HT4R stimulation is associated with an increment of cocaine- and amphetamine-regulated transcript (CART) mRNA levels both in fed and food-deprived mice (Jean et al., 2007), whereas 11

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(Geeraerts et al., 2005). Furthermore, during depression, the release of epinephrine/norepinephrine from the adrenal gland has been reported to increase beta-adrenergic activity, which then induces visceral hypersensitivity and symptoms of hard or lumpy stools in constipationpredominant IBS (Park et al., 2005). There is a growing body of evidence showing that the pathophysiology of gut diseases such as IBS and FGID involves abnormal processing of visceral nociceptive signals in the brain-gut axis, which leads to visceral hypersensitivity and hyperalgesia (Lembo et al., 1999). Hence, based on the above studies, we conclude that stress mechanism during depression may also account for abnormality in GIT function. Clinically, 5-HT stimulation has been reported to increase the secretion of aldosterone from adrenal cortex through 5-HT4R, which helps in electrolyte metabolism in the gut (Hoffman et al., 2012; Spohn et al., 2016). Moreover, 5-HT4R agonists/antagonists (Table 2) have shown an intrinsic role in GIT for augmenting the symptoms of IBS-C and IBS-D respectively (Clark, 1998; Sanger and Quigley, 2010). 5HT4R antagonists, such as SB207266, GR125487 and GR113808 decrease rectal sensitivity and small bowel transit in IBS-D patients (Clark, 1998; Houghton et al., 1999; Upadhyay, 2003). Likewise, 5-HT4R agonists RS67333, BIMU8, mosapride citrate and CJ-033466 have shown therapeutic effects on intestinal smooth muscle contractility (Bockaert et al., 2008; Clark, 1998; De Maeyer et al., 2008; Manabe et al., 2010; Sanger and Quigley, 2010). In particular, MOS and CJ030466 have been shown to be very effective after postoperative ileus (Tsuchida et al., 2011), which is an intestinal motility disorder in which monocytes/macrophages and neutrophils play crucial roles. Further, 5-

gland to modulate epinephrine secretion (Brindley et al., 2017). Paracrine regulation of adrenocortical cell activity by 5-HT involves interactions between mast cells, steroidogenic cells, and chromaffin cells (Contesse et al., 2000). Contesse et al. suggested that 5-HT released by mast cells in the vicinity of glomerulosa cells, stimulates aldosterone secretion through activation of 5-HT4R positively coupled to adenylyl cyclase and calcium influx. Concurrently, 5-HT can be metabolized by type A MAO present in the cytoplasm of intracortical chromaffin cells (Lefebvre et al., 2001). The aforementioned studies suggest that an emotional stressor can lead to significant changes in the autonomic nervous system function and adrenal secretion via alteration of 5-HT release in CNS, and thus, could alter gut function (Carney et al., 2005; Jarrett et al., 2003; Musselman and Nemeroff, 1996; Tichomirowa et al., 2005). Pathophysiology of 5-HT associated depression and comorbidity in gut, in relation to 5-HT4R function via HPA axis is illustrated in Fig. 4. The gut itself also contains a large pool of 5-HT4R in EC cells and in enteric neurons (Crowell, 2004), and can affect GIT function via intrinsic and extrinsic innervation (from CNS via the autonomic nervous system). During chronic depression, the neuroendocrine system leads the changes in the chemical environment of the GIT. EC cells sense this alteration in the chemical environment and release 5-HT in both lumen and basal space of the gut epithelium and act as a sensory transducer, which activates mucosal processes of both intrinsic and extrinsic primary afferent neurons via the trans-epithelial mechanism. 5-HT acts via 5-HTRs located on the sensory calcitonin gene-related peptide (CGRP) neurons (submucosal intrinsic primary afferent neurons), which are activated by the mucosal stimulation (Tong et al., 2011). This is followed by CGRP release that induces ACh release from cholinergic interneurons which innervate excitatory and inhibitory motor neurons and control the peristaltic and secretory reflexes (Grider, 2003). 5-HT release stimulates 5-HT4R in myenteric or submucosal interneurons, which facilitates the secretion of ACh from motor neurons and activates the prokinetic pathway. Stimulation of intrinsic primary afferent neurons activates excitatory motor neurotransmitters including ACh and substance P, and inhibitory motor neurotransmitters such as nitric oxide and vasoactive intestinal peptide (VIP) within the myenteric plexus (Gershon and Tack, 2007; Grider, 2003; Nedi et al., 2018; Schleiffer and Raul, 1997). These motor neurons innervate the smooth muscles or enterocytes and induce smooth muscle contraction and electrolyte release in the gut, which accounts for the gut peristalsis movements and food digestion (Lefebvre et al., 1998). 5-HT4R locations and actions in ENS are shown in Fig. 5. 5-HT neuron innervation and 5HT4R agonists can facilitate transmission in two groups of intrinsic interneurons, which innervate excitatory and inhibitory motor neurons in the myenteric or submucosal plexus. One group of interneurons activates excitatory motor neurons and increases the release of ACh or non-adrenergic non-cholinergic (NANC) transmitters, leading to smooth muscle contraction or stimulation of electrolyte secretion, respectively. Another group of interneurons activates inhibitory motor neurons that stimulate relaxation of smooth muscle via secreting nitric oxide or vasoactive intestinal peptides, or ATP as neurotransmitters. Additionally, in certain tissues, 5-HT can directly act on smooth muscle or enterocytes via 5-HT4R, which accounts for smooth muscle relaxation and stimulation of electrolyte secretion from enterocytes. Finally, 5-HT mediated actions in the gut are terminated by uptake into enterocytes or neurons, which is mediated by SERT (Gershon, 2004).

Fig. 4. Schematic representation of stress-induced activation of the HPA axis and its effect on GIT functioning. (1) Stress-induced imbalance in 5-HT metabolism, resultant malfunctioning of 5-HT4R in the forebrain limbic centers (such as the hypothalamus, thalamus and amygdala), (2) Stress leads to the activation of hypothalamic paraventricular nucleus (PVN) which releases the CRF to stimulate the pituitary gland for the hormone secretion, (3) The pituitary gland secretes ACTH in the blood which stimulates the adrenal gland for the hormone secretion, (4) Following ACTH stimulation, adrenal gland secretes cortisol, epinephrine, norepinephrine, and aldosterone hormones in the blood stream. Local increase of 5-HT in the adrenal gland stimulates serotonergic neurons expressing 5-HT4R which further facilitate the secretion of epinephrine, (5) Increased secretion of epinephrine affects the gut chemical environment by stimulating enterochromaffin cells and ENS. The gut contains a large pool of 5-HT4R expressing neurons in ENS. EC cells control the release of 5-HT in the gut and control the release of Ach from enteric motor neuron and control the GIT motility, (6) During the higher blood level of CRF and ACTH, adrenal gland gives negative feedback to the pituitary gland and PVN nucleus to down regulate their secretion. Blue color arrows represent the positive feedback cycle of HPA axis function. The red color arrows indicate negative feedback to pituitary and PVN nucleus.

6.3. Cumulative evidences for the pathophysiology of 5-HT4R in the gut during depression Psychological stimuli-induced hyperactivity of the neuroendocrine system may account for visceral responses in the GIT, such as stressinduced flare bowel in IBS patients (Clark, 1998; Posserud et al., 2004; Sagami et al., 2004), which is also supported by the finding of gastric sensorimotor dysfunction in patients with functional dyspepsia 12

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Fig. 5. Schematic representation of the location and effects of 5-HT4R in the ENS. 5-HT neuron innervation and 5-HT4R agonists facilitate transmission in two groups of cholinergic intrinsic interneurons, which innervate the excitatory and inhibitory motor neurons in myenteric or submucosal plexus. One group of interneurons activates excitatory motor neurons, leading to smooth muscle contraction or stimulation of electrolyte secretion via increased release of ACh or NANC (substance P), respectively. Another group of interneurons activates inhibitory motor neurons that stimulate relaxation of smooth muscle via secreting the NO or VIP, or ATP as neurotransmitters. Additionally, in certain tissues, 5HT can directly act on the smooth muscle or enterocytes via 5-HT4R, which accounts for smooth muscle relaxation and stimulation of electrolyte secretion from enterocytes. 5-HT4R activation can also sensitize CGRP containing sensory neurons by EPSP, which also activates the interneurons in myenteric or submucosa plexus. ACh: acetylcholine, ATP: Adenosine triphosphate, CGRP: calcitonin gene-related peptide, EPSP: excitatory postsynaptic potential, MR: muscarinic receptor, NANC: non-adrenergic non-cholinergic, NO: nitric oxide, NANCR: nonadrenergic non-cholinergic receptor, VIP: vasoactive intestinal peptides, VIPR: vasoactive intestinal peptide receptor.

people's lives, which leads to the progression of neurological problems including depression. In conclusion, this review provides information for a better understanding of 5-HT4R and its possible therapeutic potential in depression and associated comorbidity in the gut, via braingut axis interactions.

HT4R agonists stimulate ACh release from cholinergic myenteric neurons, which subsequently activates α7 nAChR on activated monocytes/ macrophages and inhibit their inflammatory reactions in the muscle layer and thereby ameliorates the motility disorder associated with postoperative ileus. 5-HT4R agonists, such as tegaserod, do not stimulate nociceptive extrinsic nerves nor initiate peristaltic or secretory reflexes, thus are safe and effective in the treatment of IBS with constipation (Tong et al., 2011). Treatment with 5-HT4R based therapeutics have shown a significant decrease in the symptoms of psychiatric problems, thus, proved to be significant for the treatment of inflammation and irritation in the GIT (Houghton et al., 1999; Upadhyay, 2003; Tong et al., 2011). However, the molecular mechanisms are not well studied. Therefore, exploration of drugs based on 5HT4R may discover potential therapeutic substances for the treatment of CNS diseases, which might also provide better treatment for comorbidity in the 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.

7. Concluding remarks

Acknowledgements

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 function can be severely compromised during depressive disorders, ranging from hyperactivity and hypoactivity of gut reflexes and neurotransmitter release. 5-HT4R is highly expressed both in limbic regions of the brain and GIT, thus is involved in the pathological mechanism of various psychiatric and neuronal diseases including MDD, and the associated comorbid effects on the gut, such as chronic depression-induced IBS. Additionally, during depression, 5-HT4R activates the secretion of CRF from the hypothalamic nuclei, activates the HPA axis and alters GIT function, which accounts for constipation, IBS and other gut disorders. Moreover, the role of 5-HT4R agonists/antagonists have been shown to be effective for treatment of various psychological problems including depression and gut disorders. Currently, lifestyle and socio-economic factors affect millions of

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. References Abell, T.L., Camilleri, M., DiMagno, E.P., Hench, V.S., Zinsmeister, A.R., Malagelada, J.R., 1991. Long-term efficacy of oral cisapride in symptomatic upper gut dysmotility. Dig. Dis. Sci. 36, 616–620. Agrawal, L., Vimal, S.K., Shiga, T., 2019. Role of serotonin 4 receptor in the growth of hippocampal neurons during the embryonic development in mice. Neuropharmacology 158, 107712. Akiskal, H.S., Bolis, C.L., Cazzullo, C., Costa e Silva, J.A., Gentil, V., Lecrubier, Y., Licinio, J., Linden, M., Lopez Ibor, J.J., Ndiaye, I.P., Pani, L., Prilipko, L., Robertson, M.M., Robinson, R.G., Starkstein, S.E., Thomas, P., Wang, Y., Wong, M.L., 1996. Dysthymia in neurological disorders. Mol. Psychiatry 1, 478–491.

13

Neuropharmacology 166 (2020) 107969

L. Agrawal, et al.

Busti, A.J., Murillo Jr., J.R., Cryer, B., 2004. Tegaserod-induced myocardial infarction: case report and hypothesis. Pharmacother.: J. Hum. Pharmacol. Drug Ther. 24, 526–531. Butzlaff, M., Ponimaskin, E., 2016. The role of serotonin receptors in Alzheimer's disease. Opera Med. Physiol. 2, 77–86. Camilleri, M., Di Lorenzo, C., 2012. Brain-gut axis: from basic understanding to treatment of IBS and related disorders. J. Pediatr. Gastroenterol. Nutr. 54, 446–453. Camilleri, M., Kerstens, R., Rykx, A., Vandeplassche, L., 2008. A placebo-controlled trial of prucalopride for severe chronic constipation. N. Engl. J. Med. 358, 2344–2354. Camilleri, M., Malagelada, J.R., Abell, T.L., Brown, M.L., Hench, V., Zinsmeister, A.R., 1989. Effect of six weeks of treatment with cisapride in gastroparesis and intestinal pseudoobstruction. Gastroenterology 96, 704–712. Canal, C.E., Murnane, K.S., 2017. The serotonin 5-HT(2C) receptor and the non-addictive nature of classic hallucinogens. J. Psychopharmacol. 31, 127–143. Carley, D.W., Depoortere, H., Radulovacki, M., 2001. R-zacopride, a 5-HT3 antagonist/5HT4 agonist, reduces sleep apneas in rats. Pharmacol. Biochem. Behav. 69, 283–289. Carney, R.M., Freedland, K.E., Veith, R.C., 2005. Depression, the autonomic nervous system, and coronary heart disease. Psychosom. Med. 67 (Suppl. 1), S29–S33. Chagraoui, A., Whitestone, S., Baassiri, L., Manem, J., Di Giovanni, G., De Deurwaerdère, P., 2019. Neurochemical impact of the 5-HT2C receptor agonist WAY-163909 on monoamine tissue content in the rat brain. Neurochem. Int. 124, 245–255. Choi, C.H., Kwon, J.G., Kim, S.K., Myung, S.J., Park, K.S., Sohn, C.I., Rhee, P.L., Lee, K.J., Lee, O.Y., Jung, H.K., Jee, S.R., Jeen, Y.T., Choi, M.G., Choi, S.C., Huh, K.C., Park, H., 2015. Efficacy of combination therapy with probiotics and mosapride in patients with IBS without diarrhea: a randomized, double-blind, placebo-controlled, multicenter, phase II trial. Neuro Gastroenterol. Motil. 27, 705–716. Choi, M., Zheng, H., Park, H.D., Jeong, H.K., Hong, S., Kim, J.M., Lee, D.H., 2017. Prokinetic effects of LD02GIFRO on functional gastrointestinal disorder in rats. Exp. Ther. Med. 13, 2043–2049. Ciranna, L., Catania, M.V., 2014. 5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders. Front. Cell. Neurosci. 8. Claeysen, S., Faye, P., Sebben, M., Taviaux, S., Bockaert, J., Dumuis, A., 1998. 5-HT4 receptors: cloning and expression of new splice variants. Ann. N. Y. Acad. Sci. 861, 49–56. Clark, M.S., Neumaier, J.F., 2001. The 5-HT1B receptor: behavioral implications. Psychopharmacol. Bull. 35, 170–185. Clark, R.D., 1998. Medicinal chemistry of 5-HT4 receptor ligands. In: Eglen, R.M. (Ed.), 5HT4 Receptors in the Brain and Periphery. Springer Berlin Heidelberg, Berlin, Heidelberg, pp. 1–48. Cochet, M., Donneger, R., Cassier, E., Gaven, F., Lichtenthaler, S.F., Marin, P., Bockaert, J., Dumuis, A., Claeysen, S., 2013. 5-HT4 receptors constitutively promote the nonamyloidogenic pathway of APP cleavage and interact with ADAM10. ACS Chem. Neurosci. 4, 130–140. Conductier, G., Dusticier, N., Lucas, G., Cote, F., Debonnel, G., Daszuta, A., Dumuis, A., Nieoullon, A., Hen, R., Bockaert, J., Compan, V., 2006. Adaptive changes in serotonin neurons of the raphe nuclei in 5-HT(4) receptor knock-out mouse. Eur. J. Neurosci. 24, 1053–1062. Consolo, S., Arnaboldi, S., Giorgi, S., Russi, G., Ladinsky, H., 1994. 5-HT4 receptor stimulation facilitates acetylcholine release in rat frontal cortex. Neuroreport 5, 1230–1232. Contesse, V., Lefebvre, H., Lenglet, S., Kuhn, J.-M., Delarue, C., Vaudry, H., 2000. Role of 5-HT in the regulation of the brain-pituitary-adrenal axis: effects of 5-HT on adrenocortical cells. Can. J. Physiol. Pharmacol. 78, 967–983. Coppen, A., Prange Jr., A.J., Hill, C., Whybrow, P.C., Noguera, R.R., 1972. Abnormalities of indoleamines in affective disorders. Arch. Gen. Psychiatr. 26, 474–478. Coremans, G., 2008. Prucalopride: the evidence for its use in the treatment of chronic constipation. Core Evid. 3, 45–54. Coskuner-Weber, O., Uversky, N.V., 2018. Insights into the molecular mechanisms of Alzheimer's and Parkinson's diseases with molecular simulations: understanding the roles of artificial and pathological missense mutations in intrinsically disordered proteins related to pathology. Int. J. Mol. Sci. 19. Costall, B., Domeney, A.M., Gerrard, P.A., Kelly, M.E., Naylor, R.J., 1988. Zacopride: anxiolytic profile in rodent and primate models of anxiety. J. Pharm. Pharmacol. 40, 302–305. Cote, F., Thevenot, E., Fligny, C., Fromes, Y., Darmon, M., Ripoche, M.A., Bayard, E., Hanoun, N., Saurini, F., Lechat, P., Dandolo, L., Hamon, M., Mallet, J., Vodjdani, G., 2003. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc. Natl. Acad. Sci. U. S. A. 100, 13525–13530. Coupar, I.M., Desmond, P.V., Irving, H.R., 2007. Human 5-HT(4) and 5-HT(7) receptor splice variants: are they important? Curr. Neuropharmacol. 5, 224–231. Crowell, M.D., 2004. Role of serotonin in the pathophysiology of the irritable bowel syndrome. Br. J. Pharmacol. 141, 1285–1293. Culpepper, L., Muskin, P.R., Stahl, S.M., 2015. Major depressive disorder: understanding the significance of residual symptoms and balancing efficacy with tolerability. Am. J. Med. 128, S1–S15. Dale, E., Pehrson, A., Jeyarajah, T., Li, Y., Leiser, S., Smagin, G., Olsen, C., Sánchez, C., 2016. Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function. CNS Spectr. 21, 143–161. De Maeyer, J.H., Lefebvre, R.A., Schuurkes, J.A., 2008. 5-HT4 receptor agonists: similar but not the same. Neuro Gastroenterol. Motil. 20, 99–112. De Vries, P., Willems, E.W., Heiligers, J.P., Villalón, C.M., Saxena, P.R., 1999. Investigation of the role of 5-HT1B and 5-HT1D receptors in the sumatriptan-induced constriction of porcine carotid arteriovenous anastomoses. Br. J. Pharmacol. 127, 405–412.

Alarcon de la Lastra, C., La Casa, C., Martin, M.J., Motilva, V., 1998. Effects of cinitapride on gastric ulceration and secretion in rats. Inflamm. Res. 47, 131–136. Alphin, R.S., Proakis, A.G., Leonard, C.A., Smith, W.L., Dannenburg, W.N., Kinnier, W.J., Johnson, D.N., Sancilio, L.F., Ward, J.W., 1986. Antagonism of cisplatin-induced emesis by metoclopramide and dazopride through enhancement of gastric motility. Dig. Dis. Sci. 31, 524–529. Altaf, M.A., Sood, M.R., 2008. The nervous system and gastrointestinal function. Dev. Disabil. Res. Rev. 14, 87–95. Amigo, J., Diaz, A., Pilar Cuellar, F., Vidal, R., Martin, A., Compan, V., Pazos, A., Castro, E., 2016. The absence of 5-HT4 receptors modulates depression- and anxiety-like responses and influences the response of fluoxetine in olfactory bulbectomised mice: adaptive changes in hippocampal neuroplasticity markers and 5-HT1A autoreceptor. Neuropharmacology 111, 47–58. Anisman, H., Zalcman, S., Shanks, N., Zacharko, R.M., 1992. Multisystem regulation of performance deficits induced by stressors. In: Boulton, A.A., Baker, G.B., MartinIverson, M.T. (Eds.), Animal Models in Psychiatry, II. Humana Press, Totowa, NJ, pp. 1–59. Ansorge, M.S., Zhou, M., Lira, A., Hen, R., Gingrich, J.A., 2004. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 306, 879. Antelman, S.M., Caggiula, A.R., Kiss, S., Edwards, D.J., Kocan, D., Stiller, R., 1995. Neurochemical and physiological effects of cocaine oscillate with sequential drug treatment: possibly a major factor in drug variability. Neuropsychopharmacology 12, 297–306. APA, 2015. Diagnostic and statistical manual of mental disorders (DSM-5). Alcohol. Psychiatr. Res. 51, 61–64. Artigas, F., Romero, L., de Montigny, C., Blier, P., 1996. Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci. 19, 378–383. Bang, C.S., Kim, J.H., Baik, G.H., Kim, H.S., Park, S.H., Kim, E.J., Kim, J.B., Suk, K.T., Yoon, J.H., Kim, Y.S., Kim, D.J., 2015. Mosapride treatment for functional dyspepsia: a meta-analysis. J. Gastroenterol. Hepatol. 30, 28–42. Bao, A.M., Swaab, D.F., 2019. The human hypothalamus in mood disorders: the HPA axis in the center. IBRO Rep. 6, 45–53. Baranger, K., Giannoni, P., Girard, S.D., Girot, S., Gaven, F., Stephan, D., Migliorati, M., Khrestchatisky, M., Bockaert, J., Marchetti-Gauthier, E., Rivera, S., Claeysen, S., Roman, F.S., 2017. Chronic treatments with a 5-HT4 receptor agonist decrease amyloid pathology in the entorhinal cortex and learning and memory deficits in the 5xFAD mouse model of Alzheimer's disease. Neuropharmacology 126, 128–141. Becker, D.P., Flynn, D.L., Moormann, A.E., Nosal, R., Villamil, C.I., Loeffler, R., Gullikson, G.W., Moummi, C., Yang, D.C., 2006. Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists. J. Med. Chem. 49, 1125–1139. Belujon, P., Grace, A.A., 2017. Dopamine system dysregulation in major depressive disorders. Int. J. Neuropsychopharmacol. 20, 1036–1046. Bel, N., Artigas, F., 1999. Modulation of the extracellular 5-hydroxytryptamine brain concentrations by the serotonin and noradrenaline reuptake inhibitor, milnacipran microdialysis studies in rats. Neuropsychopharmacology 21, 745–754. Benazzi, F., 2006. Various forms of depression. Dialogues Clin. Neurosci. 8, 151–161. Bharucha, A.E., Camilleri, M., Haydock, S., Ferber, I., Burton, D., Cooper, S., Tompson, D., Fitzpatrick, K., Higgins, R., Zinsmeister, A.R., 2000. Effects of a serotonin 5-HT(4) receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans. Gut 47, 667–674. Blondel, O., Gastineau, M., Langlois, M., Fischmeister, R., 1998. The 5-HT4 receptor antagonist ML10375 inhibits the constitutive activity of human 5-HT4(c) receptor. Br. J. Pharmacol. 125, 595–597. Bockaert, J., Claeysen, S., Compan, V., Dumuis, A., 2004. 5-HT4 receptors. Curr. Drug Targets - CNS Neurol. Disord. 3, 39–51. Bockaert, J., Claeysen, S., Compan, V., Dumuis, A., 2008. 5-HT(4) receptors: history, molecular pharmacology and brain functions. Neuropharmacology 55, 922–931. Bockaert, J., Dumuis, A., 1998. Localization of 5-HT4 receptors in vertebrate brain and their potential behavioral roles. In: Eglen, R.M. (Ed.), 5-HT4 Receptors in the Brain and Periphery. Springer Berlin Heidelberg, Berlin, Heidelberg, pp. 63–86. Boullin, D.J., 1964. Obsdrvaions on the significance of 5-hydroxytryptamine in relation to the peristaltic reflex of the rat. Br. J. Pharmacol. Chemother. 23, 14–33. Brattelid, T., Kvingedal, A.M., Krobert, K.A., Andressen, K.W., Bach, T., Hystad, M.E., Kaumann, A.J., Levy, F.O., 2004. Cloning, pharmacological characterisation and tissue distribution of a novel 5-HT4 receptor splice variant, 5-HT4(i). Naunyn Schmiedeberg's Arch. Pharmacol. 369, 616–628. Bremner, J.D., Narayan, M., Anderson, E.R., Staib, L.H., Miller, H.L., Charney, D.S., 2000. Hippocampal volume reduction in major depression. Am. J. Psychiatry 157, 115–118. Brindley, R.L., Bauer, M.B., Blakely, R.D., Currie, K.P.M., 2017. Serotonin and serotonin transporters in the adrenal Mmedulla: a potential hub for modulation of the sympathetic stress response. ACS Chem. Neurosci. 8, 943–954. Brown, A.S., Gershon, S., 1993. Dopamine and depression. J. Neural Transm. Gen. Sect. 91, 75–109. Browning, K.N., Verheijden, S., Boeckxstaens, G.E., 2017. The vagus nerve in appetite regulation, mood, and intestinal inflammation. Gastroenterology 152, 730–744. Brunello, N., Akiskal, H., Boyer, P., Gessa, G.L., Howland, R.H., Langer, S.Z., Mendlewicz, J., Paes de Souza, M., Placidi, G.F., Racagni, G., Wessely, S., 1999. Dysthymia: clinical picture, extent of overlap with chronic fatigue syndrome, neuropharmacological considerations, and new therapeutic vistas. J. Affect. Disord. 52, 275–290. Buckley, U., Shivkumar, K., 2016. Stress-induced cardiac arrhythmias: the heart-brain interaction. Trends Cardiovasc. Med. 26, 78–80. Bulbring, E., Lin, R.C., Schofield, G., 1958. An investigation of the peristaltic reflex in relation to anatomical observations. Q. J. Exp. Physiol. Cogn. Med. Sci. 43, 26–37. Bureau, R., Boulouard, M., Dauphin, F., Lezoualc'h, F., Rault, S., 2010. Review of 5-HT4R ligands: state of art and clinical applications. Curr. Top. Med. Chem. 10, 527–553.

14

Neuropharmacology 166 (2020) 107969

L. Agrawal, et al.

3066–3074. Hagena, H., Manahan-Vaughan, D., 2017. The serotonergic 5-HT4 receptor: a unique modulator of hippocampal synaptic information processing and cognition. Neurobiol. Learn. Mem. 138, 145–153. Hallerback, B.I., Bommelaer, G., Bredberg, E., Campbell, M., Hellblom, M., Lauritsen, K., Wienbeck, M., Holmgren, L.L., 2002. Dose finding study of mosapride in functional dyspepsia: a placebo-controlled, randomized study. Aliment. Pharmacol. Ther. 16, 959–967. Hammerle, C.W., Surawicz, C.M., 2008. Updates on treatment of irritable bowel syndrome. World J. Gastroenterol. 14, 2639–2649. Hannon, J., Hoyer, D., 2008. Molecular biology of 5-HT receptors. Behav. Brain Res. 195, 198–213. Harbuz, M.S., Perveen-Gill, Z., Lalies, M.D., Jessop, D.S., Lightman, S.L., Chowdrey, H.S., 1996. The role of endogenous serotonin in adjuvant-induced arthritis in the rat. Br. J. Rheumatol. 35, 112–116. Haug, T.T., Mykletun, A., Dahl, A.A., 2002. Are anxiety and depression related to gastrointestinal symptoms in the general population? Scand. J. Gastroenterol. 37, 294–298. Hedlund, P.B., 2009. The 5-HT7 receptor and disorders of the nervous system: an overview. Psychopharmacology 206, 345–354. Hegde, S.S., Eglen, R.M., 1996. Peripheral 5-HT4 receptors. FASEB (Fed. Am. Soc. Exp. Biol.) J. 10, 1398–1407. Herman, J.P., Figueiredo, H., Mueller, N.K., Ulrich-Lai, Y., Ostrander, M.M., Choi, D.C., Cullinan, W.E., 2003. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness. Front. Neuroendocrinol. 24, 151–180. Hieronymus, F., Lisinski, A., Nilsson, S., Eriksson, E., 2018. Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression. Mol Psychiatry 23 (8), 1731–1736. https://doi.org/ 10.1038/mp.2017.147. Hillhouse, T.M., Porter, J.H., 2015. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp. Clin. Psychopharmacol 23, 1–21. Ho, S.S.N., Chow, B.K.C., Yung, W.-H., 2007. Serotonin increases the excitability of the hypothalamic paraventricular nucleus magnocellular neurons. Eur. J. Neurosci. 25, 2991–3000. Hoffman, J.M., Tyler, K., MacEachern, S.J., Balemba, O.B., Johnson, A.C., Brooks, E.M., Zhao, H., Swain, G.M., Moses, P.L., Galligan, J.J., Sharkey, K.A., Greenwood-Van Meerveld, B., Mawe, G.M., 2012. Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 142, 844–854 e844. Holtmann, G., Siffert, W., Haag, S., Mueller, N., Langkafel, M., Senf, W., Zotz, R., Talley, N.J., 2004. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology 126, 971–979. Houghton, L.A., Jackson, N.A., Whorwell, P.J., Cooper, S.M., 1999. 5-HT4 receptor antagonism in irritable bowel syndrome: effect of SB-207266-A on rectal sensitivity and small bowel transit. Aliment. Pharmacol. Ther. 13, 1437–1444. Howland, R.H., Thase, M.E., 1991. Biological studies of dysthymia. Biol. Psychiatry 30, 283–304. Israelyan, N., Del Colle, A., Li, Z., Park, Y., Xing, A., Jacobsen, J.P.R., Luna, R.A., Jensen, D.D., Madra, M., Saurman, V., Rahim, R., Latorre, R., Law, K., Carson, W., Bunnett, N.W., Caron, M.G., Margolis, K.G., 2019. Effects of serotonin and slow-release 5hydroxytryptophan on gastrointestinal motility in a mouse model of depression. Gastroenterology 157, 507–521 e504. Jarrett, M.E., Burr, R.L., Cain, K.C., Hertig, V., Weisman, P., Heitkemper, M.M., 2003. Anxiety and depression are related to autonomic nervous system function in women with irritable bowel syndrome. Dig. Dis. Sci. 48, 386–394. Jean, A., Conductier, G., Manrique, C., Bouras, C., Berta, P., Hen, R., Charnay, Y., Bockaert, J., Compan, V., 2007. Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens. Proc. Natl. Acad. Sci. 104, 16335. Jimerson, D.C., 1987. Role of dopamine mechanisms in the affective disorders. In: Meltzer, H.Y. (Ed.), Psychopharmacology: the Third Generation of Progress. Raven Press, New York, pp. 505–511. Joubert, L., Hanson, B., Barthet, G., Sebben, M., Claeysen, S., Hong, W., Marin, P., Dumuis, A., Bockaert, J., 2004. New sorting nexin (SNX27) and NHERF specifically interact with the 5-HT4a receptor splice variant: roles in receptor targeting. J. Cell Sci. 117, 5367–5379. Kahrilas, P.J., Quigley, E.M.M., Castell, D.O., Spechler, S.J., 2000. The effects of tegaserod (HTF 919) on oesophageal acid exposure in gastro-oesophageal reflux disease. Aliment. Pharmacol. Ther. 14, 1503–1509. Kaumann, A.J., Medhurst, A.D., Boyland, P., Vimal, M., Young, R.C., 1993. SB 203186: a potent 5-HT4 antagonist for cardiac 5-HT4 receptors. In: Vanhoutte PM Saxena, P.R., Paoletti, R., Brunello, N., Jackson, A.S. (Eds.), Serotonin: from Cell Biology to Pharmacology and Therapeutics. Springer Netherlands, Dordrecht, pp. 135–139. Keller, M.B., Shapiro, R.W., 1982. “Double depression”: superimposition of acute depressive episodes on chronic depressive disorders. Am. J. Psychiatry 139, 438–442. Kennett, G.A., Bright, F., Blackburn, T.P., Sanger, G.J., 1997. Anxiolytic-like actions of the selective 5-HT4 receptor antagonists SB 204070A and SB 207266A in rats. Neuropharmacology 36, 707–712. Khazaeipour, Z., Taheri-Otaghsara, S.-M., Naghdi, M., 2015. Depression following spinal cord injury: its relationship to demographic and socioeconomic indicators. Top. Spinal Cord Inj. Rehabil. 21, 149–155. Kjekshus, J.K., Torp-Pedersen, C., Gullestad, L., Køber, L., Edvardsen, T., Olsen, I.C., Sjaastad, I., Qvigstad, E., Skomedal, T., Osnes, J.-B., Levy, F.O., 2009. Effect of piboserod, a 5-HT4 serotonin receptor antagonist, on left ventricular function in patients with symptomatic heart failure. Eur. J. Heart Fail. 11, 771–778.

Di Giovanni, G., De Deurwaerdère, P., 2016. New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders. Pharmacol. Ther. 157, 125–162. Diaz, S.L., Doly, S., Narboux-Nême, N., Fernández, S., Mazot, P., Banas, S.M., Boutourlinsky, K., Moutkine, I., Belmer, A., Roumier, A., Maroteaux, L., 2012. 5HT(2B) receptors are required for serotonin-selective antidepressant actions. Mol. Psychiatry 17, 154–163. Dumuis, A., Bouhelal, R., Sebben, M., Cory, R., Bockaert, J., 1988. A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. Mol. Pharmacol. 34, 880–887. Eglen, R.M., Alvarez, R., Johnson, L.G., Leung, E., Wong, E.H., 1993. The action of SDZ 205,557 at 5-hydroxytryptamine (5-HT3 and 5-HT4) receptors. Br. J. Pharmacol. 108, 376–382. Fagni, L., Dumuis, A., Sebben, M., Bockaert, J., 1992. The 5-HT4 receptor subtype inhibits K+ current in colliculi neurones via activation of a cyclic AMP-dependent protein kinase. Br. J. Pharmacol. 105, 973–979. Feldman, S., Conforti, N., Melamed, E., 1987. Paraventricular nucleus serotonin mediates neurally stimulated adrenocortical secretion. Brain Res. Bull. 18, 165–168. Feldman, S., Weidenfeld, J., 1997. Hypothalamic mechanisms mediating glutamate effects on the hypothalamo-pituitary-adrenocortical axis. J. Neural Transm. 104, 633–642. Feldman, S., Weidenfeld, J., 1998. The excitatory effects of the amygdala on hypothalamo-pituitary-adrenocortical responses are mediated by hypothalamic norepinephrine, serotonin, and CRF-41. Brain Res. Bull. 45, 389–393. Fontana, D.J., Daniels, S.E., Wong, E.H.F., Clark, R.D., Eglen, R.M., 1997. The effects of novel, selective 5-hydroxytryptamine (5-HT) 4 receptor ligands in rat spatial navigation. Neuropharmacology 36, 689–696. Foster, J.A., McVey Neufeld, K.-A., 2013. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 36, 305–312. Furlotti, G., Alisi, M.A., Apicella, C., Capezzone de Joannon, A., Cazzolla, N., Costi, R., Cuzzucoli Crucitti, G., Garrone, B., Iacovo, A., Magaro, G., Mangano, G., Miele, G., Ombrato, R., Pescatori, L., Polenzani, L., Rosi, F., Vitiello, M., Di Santo, R., 2012. Discovery and pharmacological profile of new 1H-indazole-3-carboxamide and 2Hpyrrolo[3,4-c]quinoline derivatives as selective serotonin 4 receptor ligands. J. Med. Chem. 55, 9446–9466. Furness, J.B., 2012. The enteric nervous system and neurogastroenterology. Nat. Rev. Gastroenterol. Hepatol. 9, 286. Gale, J.D., Grossman, C.J., Whitehead, J.W., Oxford, A.W., Bunce, K.T., Humphrey, P.P., 1994. GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor. Br. J. Pharmacol. 111, 332–338. Garcia-Garcia, A.L., Newman-Tancredi, A., Leonardo, E.D., 2014. 5-HT(1A) [corrected] receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function. Psychopharmacology 231, 623–636. Gardner, M., Lightman, S., Kuh, D., Comijs, H., Deeg, D., Gallacher, J., Geoffroy, M.-C., Kivimaki, M., Kumari, M., Power, C., Hardy, R., Richards, M., Ben-Shlomo, Y., 2019. Dysregulation of the hypothalamic pituitary adrenal (HPA) axis and cognitive capability at older ages: individual participant meta-analysis of five cohorts. Sci. Rep. 9, 4555. Gaster, L.M., King, F.D., 1997. Serotonin 5-HT3 and 5-HT4 receptor antagonists. Med. Res. Rev. 17, 163–214. Geeraerts, B., Vandenberghe, J., Van Oudenhove, L., Gregory, L.J., Aziz, Q., Dupont, P., Demyttenaere, K., Janssens, J., Tack, J., 2005. Influence of experimentally induced anxiety on gastric sensorimotor function in humans. Gastroenterology 129, 1437–1444. Geng, F., Tian, J., Wu, J.-L., Luo, Y., Zou, W.-J., Peng, C., Lu, G.-F., 2018. Dorsomedial prefrontal cortex 5-HT6 receptors regulate anxiety-like behavior. Cognit. Affect Behav. Neurosci. 18, 58–67. Gershon, M.D., 2004. Review article: serotonin receptors and transporters — roles in normal and abnormal gastrointestinal motility. Aliment. Pharmacol. Ther. 20, 3–14. Gershon, M.D., 2013. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr. Opin. Endocrinol. Diabetes Obes. 20, 14–21. Gershon, M.D., Tack, J., 2007. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132, 397–414. Giannoni, P., Gaven, F., de Bundel, D., Baranger, K., Marchetti-Gauthier, E., Roman, F.S., Valjent, E., Marin, P., Bockaert, J., Rivera, S., Claeysen, S., 2013. Early administration of RS 67333, a specific 5-HT4 receptor agonist, prevents amyloidogenesis and behavioral deficits in the 5XFAD mouse model of Alzheimer's disease. Front. Aging Neurosci. 5, 96. Gillig, P.M., Sanders, R.D., 2010. Cranial nerves IX, X, XI, and XII. Psychiatry 7, 37–41. Gillman, P.K., 2007. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br. J. Pharmacol. 151, 737–748. Gonzalez, R., Chavez-Pascacio, K., Meneses, A., 2013. Role of 5-HT5A receptors in the consolidation of memory. Behav. Brain Res. 252, 246–251. Grailhe, R.W., Grabtree, G., Hen, R., 2001. Human 5-HT5 receptors: the 5-HT5A receptor is functional but the 5-HT5B receptor was lost during mammalian evolution. Eur. J. Pharmacol. 418, 157–167. Green, A.R., 2006. Neuropharmacology of 5-hydroxytryptamine. Br. J. Pharmacol. 147 (Suppl. 1), 145–152. Grider, J.R., 2003. Neurotransmitters mediating the intestinal peristaltic reflex in the mouse. J. Pharmacol. Exp. Ther. 307, 460–467. Griffiths, J., V Ravindran, A., Merali, Z., Anisman, H., 2000. Dysthymia: a review of pharmacological and behavioral factors. Mol. Psychiatry 5, 242–261. Guiard, B.P., Giovanni, G.D., 2015. Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link? Front. Pharmacol. 6, 1–17. Haahr, M.E., Fisher, P., Holst, K., Madsen, K., Jensen, C.G., Marner, L., Lehel, S., Baare, W., Knudsen, G., Hasselbalch, S., 2013. The 5-HT4 receptor levels in hippocampus correlates inversely with memory test performance in humans. Hum. Brain Mapp. 34,

15

Neuropharmacology 166 (2020) 107969

L. Agrawal, et al.

dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology 99, S18–S27. Mendez-David, I., David, D.J., Darcet, F., Wu, M.V., Kerdine-Römer, S., Gardier, A.M., Hen, R., 2014. Rapid anxiolytic effects of a 5-HT₄ receptor agonist are mediated by a neurogenesis-independent mechanism. Neuropsychopharmacology 39, 1366–1378. Meneses, A., 2014a. 5-HT7 receptor stimulation and blockade: a therapeutic paradox about memory formation and amnesia. Front. Behav. Neurosci. 8 207-207. Meneses, A., 2014b. Chapter 4 - 5-HT1A receptor. In: Meneses, A. (Ed.), The Role of 5-HT Systems on Memory and Dysfunctional Memory. Academic Press, San Diego, pp. 17–21. Meneses, A., 2014c. Chapter 5 - 5-HT1B receptor. In: Meneses, A. (Ed.), The Role of 5-HT Systems on Memory and Dysfunctional Memory. Academic Press, San Diego, pp. 23–25. Meneses, A., 2014d. Chapter 6 - 5-HT1E/1F receptor. In: Meneses, A. (Ed.), The Role of 5HT Systems on Memory and Dysfunctional Memory. Academic Press, San Diego, pp. 27–28. Meneses, A., 2014e. Chapter 7 - 5-HT2A/2B/2C receptor. In: Meneses, A. (Ed.), The Role of 5-HT Systems on Memory and Dysfunctional Memory. Academic Press, San Diego, pp. 29–33. Meneses, A., 2014f. Chapter 8 - 5-HT3 receptor. In: Meneses, A. (Ed.), The Role of 5-HT Systems on Memory and Dysfunctional Memory. Academic Press, San Diego, pp. 35–38. Meneses, A., 2014g. Chapter 9 - 5-HT4 receptor. In: Meneses, A. (Ed.), The Role of 5-HT Systems on Memory and Dysfunctional Memory. Academic Press, San Diego, pp. 39–43. Meneses, A., 2014h. Chapter 10 - 5-HT5 receptor. In: Meneses, A. (Ed.), The Role of 5-HT Systems on Memory and Dysfunctional Memory. Academic Press, San Diego, pp. 45–48. Meneses, A., 2014i. Chapter 11 - 5-HT6 receptor. In: Meneses, A. (Ed.), The Role of 5-HT Systems on Memory and Dysfunctional Memory. Academic Press, San Diego, pp. 49–52. Meneses, A., 2014j. Chapter 12 - 5-HT7 receptor. In: Meneses, A. (Ed.), The Role of 5-HT Systems on Memory and Dysfunctional Memory. Academic Press, San Diego, pp. 53–64. Meneses, A., Hong, E., 1997. Effects of 5-HT4 receptor agonists and antagonists in learning. Pharmacol. Biochem. Behav. 56, 347–351. Meyer, L.C., Fuller, A., Mitchell, D., 2006. Zacopride and 8-OH-DPAT reverse opioidinduced respiratory depression and hypoxia but not catatonic immobilization in goats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290, R405–R413. Minami, M., Endo, T., Tamakai, H., Ogawa, T., Hamaue, N., Hirafuji, M., Monma, Y., Yoshioka, M., Hagihara, K., 1997. Antiemetic effects of N-3389, a newly synthesized 5-HT3 and 5-HT4 receptor antagonist, in ferrets. Eur. J. Pharmacol. 321, 333–342. Miner, W., Sanger, G., Turner, D., 1986. Comparison of the effect of BRL 24924, metoclopramide and domperidone on cisplatin-induced emesis in the ferret. Br. J. Pharmacol. 88, 374. Miner, W.D., Sanger, G.J., Turner, D.H., 1987. Evidence that 5-hydroxytryptamine3 receptors mediate cytotoxic drug and radiation-evoked emesis. Br. J. Canc. 56, 159–162. Mohler, E.G., Shacham, S., Noiman, S., Lezoualc'h, F., Robert, S., Gastineau, M., Rutkowski, J., Marantz, Y., Dumuis, A., Bockaert, J., Gold, P.E., Ragozzino, M.E., 2007. VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux. Neuropharmacology 53, 563–573. Moloney, R.D., O'Mahony, S.M., Dinan, T.G., Cryan, J.F., 2015. Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities. Front. Psychiatry 6. Musselman, D.L., Nemeroff, C.B., 1996. Depression and endocrine disorders: focus on the thyroid and adrenal system. Br. J. Psychiatry 168, 123–128. Nautiyal, K.M., Hen, R., 2017. Serotonin receptors in depression: from A to B. F1000 Res. 6, 123. Nedi, T., White, P.J., Coupar, I.M., Irving, H.R., 2018. Effect of the 5-HT4 receptor agonist tegaserod on the expression of GRK2 and GRK6 in the rat gastrointestinal tract. BMC Res. Notes 11, 362. Nikiforuk, A., 2015. Targeting the serotonin 5-HT7 receptor in the search for treatments for CNS disorders: rationale and progress to date. CNS Drugs 29, 265–275. Ohtsuki, T., Ishiguro, H., Detera-Wadleigh, S.D., Toyota, T., Shimizu, H., Yamada, K., Yoshitsugu, K., Hattori, E., Yoshikawa, T., Arinami, T., 2002. Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese casecontrol samples and the NIMH Genetics Initiative Bipolar Pedigrees. Mol. Psychiatry 7, 954. Orsetti, M., Dellarole, A., Ferri, S., Ghi, P., 2003. Acquisition, retention, and recall of memory after injection of RS67333, a 5-HT(4) receptor agonist, into the nucleus basalis magnocellularis of the rat. Learn. Mem. 10, 420–426. Padayatti, P.S., Wang, L., Gupta, S., Orban, T., Sun, W., Salom, D., Jordan, S.R., Palczewski, K., Chance, M.R., 2013. A hybrid structural approach to analyze ligand binding by the serotonin type 4 receptor (5-HT4). Mol. Cell. Proteom. 12, 1259–1271. Pan, L., Gilbert, F., 1992. Activation of 5-HT1A receptor subtype in the paraventricular nuclei of the hypothalamus induces CRH and ACTH release in the rat. Neuroendocrinology 56, 797–802. Park, J.H., Rhee, P.L., Kim, H.S., Lee, J.H., Kim, Y.H., Kim, J.J., Rhee, J.C., Kang, E.H., Yu, B.H., 2005. Increased beta-adrenergic sensitivity correlates with visceral hypersensitivity in patients with constipation-predominant irritable bowel syndrome. Dig. Dis. Sci. 50, 1454–1460. Pata, C., Erdal, M.E., Derici, E., Yazar, A., Kanik, A., Ulu, O., 2002. Serotonin transporter gene polymorphism in irritable bowel syndrome. Am. J. Gastroenterol. 97, 1780–1784. Paz-Filho, G., Mastronardi, C.A., 2014. Interactions between the endocrine system and the gastrointestinal tract. Transl. Gastrointest. Cancer 4, 1–2.

Klein, D.N., Kocsis, J.H., McCullough, J.P., Holzer 3rd, C.E., Hirschfeld, R.M., Keller, M.B., 1996. Symptomatology in dysthymic and major depressive disorder. Psychiatr. Clin. N. Am. 19, 41–53. Klein, M.T., Teitler, M., 2012. Distribution of 5-ht(1E) receptors in the mammalian brain and cerebral vasculature: an immunohistochemical and pharmacological study. Br. J. Pharmacol. 166, 1290–1302. Komada, T., Yano, S., 2007. Pharmacological characterization of 5-hydroxytryptaminereceptor subtypes in circular muscle from the rat stomach. Biol. Pharm. Bull. 30, 508–513. Kozono, N., Ohtani, A., Shiga, T., 2017. Roles of the serotonin 5-HT4 receptor in dendrite formation of the rat hippocampal neurons in vitro. Brain Res. 1655, 114–121. Laflamme, N., Feuvrier, E., Richard, D., Rivest, S., 1999. Involvement of serotonergic pathways in mediating the neuronal activity and genetic transcription of neuroendocrine corticotropin-releasing factor in the brain of systemically endotoxinchallenged rats. Neuroscience 88, 223–240. Lalut, J., Karila, D., Dallemagne, P., Rochais, C., 2017. Modulating 5-HT4 and 5-HT6 receptors in Alzheimer's disease treatment. Future Med. Chem. 9, 781–795. Lau, J., Herzog, H., 2014. CART in the regulation of appetite and energy homeostasis. Front. Neurosci. 8. Lee, A., Kuo, B., 2010. Metoclopramide in the treatment of diabetic gastroparesis. Expert Rev. Endocrinol. Metab. 5, 653–662. Lefebvre, H., Compagnon, P., Contesse, V., Delarue, C., Thuillez, C., Vaudry, H., Kuhn, J.M., 2001. Production and metabolism of serotonin (5-HT) by the human adrenal cortex: paracrine stimulation of aldosterone secretion by 5-HT. J. Clin. Endocrinol. Metab. 86, 5001–5007. Lefebvre, H., Contesse, V., Delarue, C., Soubrane, C., Legrand, A., Kuhn, J.M., Wolf, L.M., Vaudry, H., 1993. Effect of the serotonin-4 receptor agonist zacopride on aldosterone secretion from the human adrenal cortex: in vivo and in vitro studies. J. Clin. Endocrinol. Metab. 77, 1662–1666. Lefebvre, H.C.V., Delarue, C., Kuhn, J.M., Vaudry, H., 1998. The 5-HT4 receptor in the adrenal gland. In: E, R.M. (Ed.), 5-HT4 Receptors in the Brain and Periphery. Springer, Berlin, Heidelberg Biotechnology Intelligence Unit. Lembo, T., Naliboff, B., Munakata, J., Fullerton, S., Saba, L., Tung, S., Schmulson, M., Mayer, E.A., 1999. Symptoms and visceral perception in patients with pain-predominant irritable bowel syndrome. Am. J. Gastroenterol. 94, 1320–1326. Li, Z., Chalazonitis, A., Huang, Y.Y., Mann, J.J., Margolis, K.G., Yang, Q.M., Kim, D.O., Cote, F., Mallet, J., Gershon, M.D., 2011. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J. Neurosci. 31, 8998–9009. Liu, M.T., Kuan, Y.H., Wang, J., Hen, R., Gershon, M.D., 2009. 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J. Neurosci. 29, 9683–9699. Liu, Z., Sakakibara, R., Odaka, T., Uchiyama, T., Uchiyama, T., Yamamoto, T., Ito, T., Asahina, M., Yamaguchi, K., Yamaguchi, T., Hattori, T., 2005. Mosapride citrate, a novel 5-HT4 agonist and partial 5-HT3 antagonist, ameliorates constipation in parkinsonian patients. Mov. Disord. 20, 680–686. Lopez-Rodriguez, M., Benhamu, B., Morcillo, M., Murcia, M., Viso, A., Campillo, M., Pardo, L., 2002. 5-HT4 receptor antagonists: structure-affinity relationships and ligand-receptor interactions. Curr. Top. Med. Chem. 2, 625–641. Lowry, C., 2002. Functional subsets of serotonergic neurones: implications for control of the hypothalamic‐pituitary‐adrenal axis. J. Neuroendocrinol. 14, 911–923. Lucas, G., Rymar, V.V., Du, J., Mnie-Filali, O., Bisgaard, C., Manta, S., Lambas-Senas, L., Wiborg, O., Haddjeri, N., Pineyro, G., Sadikot, A.F., Debonnel, G., 2007. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 55, 712–725. Lummis, S.C.R., 2012. 5-HT(3) receptors. J. Biol. Chem. 287, 40239–40245. Lyubashina, O., Busygina, I., Sivachenko, I., Panteleev, S., 2016. The 5-HT4 receptor agonists prucalopride and BIMU8 suppress abdominal nociception in animal models. FASEB J. 30 927.929-927.929. Maas, J.W., 1975. Biogenic amines and depression: biochemical and pharmacological separation of two types of depression. Arch. Gen. Psychiatr. 32, 1357–1361. Mackie, A.D., Ferrington, C., Cowan, S., Merrick, M.V., Baird, J.D., Palmer, K.R., 1991. The effects of renzapride, a novel prokinetic agent, in diabetic gastroparesis. Aliment. Pharmacol. Ther. 5, 135–142. Madsen, K., Torstensen, E., Holst, K.K., Haahr, M.E., Knorr, U., Frokjaer, V.G., BrandtLarsen, M., Iversen, P., Fisher, P.M., Knudsen, G.M., 2014. Familial risk for major depression is associated with lower striatal 5-HT₄ receptor binding. Int. J. Neuropsychopharmacol. 18, pyu034. Malberg, J.E., Eisch, A.J., Nestler, E.J., Duman, R.S., 2000. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104–9110. Manabe, N., Wong, B.S., Camilleri, M., 2010. New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders. Expert Opin. Investig. Drugs 19, 765–775. Manzke, T., Guenther, U., Ponimaskin, E.G., Haller, M., Dutschmann, M., Schwarzacher, S., Richter, D.W., 2003. 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia. Science 301, 226. Marazziti, D., 2017. Understanding the role of serotonin in psychiatric diseases. F1000Research 6 180-180. Mathews, D.C., Henter, I.D., Zarate, C.A., 2012. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs 72, 1313–1333. Mayer, E.A., Craske, M., Naliboff, B.D., 2001. Depression, anxiety, and the gastrointestinal system. J. Clin. Psychiatr. 62 (Suppl. 8), 28–36 discussion 37. Mayer, E.A., Tillisch, K., 2011. The brain-gut axis in abdominal pain syndromes. Annu. Rev. Med. 62, 381–396. Meltzer, H.Y., 1989. Clinical studies on the mechanism of action of clozapine: the

16

Neuropharmacology 166 (2020) 107969

L. Agrawal, et al.

Sansone, R.A., Sansone, L.A., 2009. Dysthymic disorder: forlorn and overlooked? Psychiatry 6 (5), 46–51. Sarchiapone, M., Gramaglia, C., Iosue, M., Carli, V., Mandelli, L., Serretti, A., Marangon, D., Zeppegno, P., 2018. The association between electrodermal activity (EDA), depression and suicidal behaviour: a systematic review and narrative synthesis. BMC Psychiatry 18, 22. Schleiffer, R., Raul, F., 1997. Nitric oxide and the digestive system in mammals and nonmammalian vertebrates. Comp. Biochem. Physiol. Physiol. 118, 965–974. Shah, E., Rezaie, A., Riddle, M., Pimentel, M., 2014. Psychological disorders in gastrointestinal disease: epiphenomenon, cause or consequence? Ann. Gastroenterol. 27, 224–230. Siever, L.J., 1987. Role of noradrenergic mechanisms in the etiology of the affective disorders. In: Meltzer, H.Y. (Ed.), Psychopharmacology: the Third Generation of Progress. Raven, New York, pp. 493–504. Simmons, W.K., Burrows, K., Avery, J.A., Kerr, K.L., Bodurka, J., Savage, C.R., Drevets, W.C., 2016. Depression-related increases and decreases in appetite: dissociable patterns of aberrant activity in reward and interoceptive neurocircuitry. Am. J. Psychiatry 173, 418–428. Siniscalchi, A., Badini, I., Beani, L., Bianchi, C., 1999. 5-HT4 receptor modulation of acetylcholine outflow in Guinea pig brain slices. Neuroreport 10, 547–551. Skingle, M., Beattie, D., Scopes D, I.C., J Starkey, S., E Connor, H., Feniuk, W., Tyers, M.B., 1996. GR127935: a potent and selective 5-HT1D receptor antagonist. Behav. Brain Res. 73, 157–161. Smith, S.M., Vale, W.W., 2006. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin. Neurosci. 8, 383–395. Smith, W.L., Alphin, R.S., Jackson, C.B., Sancilio, L.F., 1989. The antiemetic profile of zacopride. J. Pharm. Pharmacol. 41, 101–105. Smriga, M., Ando, T., Akutsu, M., Furukawa, Y., Miwa, K., Morinaga, Y., 2007. Oral treatment with L-lysine and L-arginine reduces anxiety and basal cortisol levels in healthy humans. Biomed. Res. 28, 85–90. Smriga, M., Torii, K., 2003. L-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats. Proc. Natl. Acad. Sci. U. S. A 100, 15370–15375. Snape Jr., W.J., Battle, W.M., Schwartz, S.S., Braunstein, S.N., Goldstein, H.A., Alavi, A., 1982. Metoclopramide to treat gastroparesis due to diabetes mellitus: a double-blind, controlled trial. Ann. Intern. Med. 96, 444–446. Spohn, S.N., Bianco, F., Scott, R.B., Keenan, C.M., Linton, A.A., O'Neill, C.H., Bonora, E., Dicay, M., Lavoie, B., Wilcox, R.L., MacNaughton, W.K., De Giorgio, R., Sharkey, K.A., Mawe, G.M., 2016. Protective actions of epithelial 5-hydroxytryptamine 4 receptors in normal and inflamed colon. Gastroenterology 151, 933–944 e933. Srivijaya, R., Vishweshwar, P., Sreekanth, B.R., Vyas, K., 2008. Crystalline forms and aqueous solubilities of an IBS drug, tegaserod. CrystEngComm 10, 283–287. Stakenborg, N., Di Giovangiulio, M.E., Boeckxstaens, G., Matteoli, G., 2013. The versatile role of the vagus nerve in the gastrointestinal tract. EMJ Gastroenterol. 1, 106–114. Stanghellini, V., 1999. Three-month prevalence rates of gastrointestinal symptoms and the influence of demographic factors: results from the domestic/international gastroenterology surveillance study (DIGEST). Scand. J. Gastroenterol. 34 (231), 20–28. Stanley, S.A., Small, C.J., Murphy, K.G., Rayes, E., Abbott, C.R., Seal, L.J., Morgan, D.G.A., Sunter, D., Dakin, C.L., Kim, M.S., Hunter, R., Kuhar, M., Ghatei, M.A., Bloom, S.R., 2001. Actions of cocaine- and amphetamine-regulated transcript (CART) peptide on regulation of appetite and hypothalamo–pituitary axes in vitro and in vivo in male rats. Brain Res. 893, 186–194. Stenbæk, D.S., Fisher, P.M., Ozenne, B., Andersen, E., Hjordt, L.V., McMahon, B., Hasselbalch, S.G., Frokjaer, V.G., Knudsen, G.M., 2017. Brain serotonin 4 receptor binding is inversely associated with verbal memory recall. Brain Behav. 7, e00674. Sulser, F., 1984. Regulation and function of noradrenaline receptor systems in brain. Psychopharmacological aspects. Neuropharmacology 23, 255–261. Švob Štrac, D., Pivac, N., Mück-Šeler, D., 2016. The serotonergic system and cognitive function. Transl. Neurosci. 7, 35–49. Tack, J., Coremans, G., Janssens, J., 1995. A risk-benefit assessment of cisapride in the treatment of gastrointestinal disorders. Drug Saf. 12, 384–392. Tack, J., van Outryve, M., Beyens, G., Kerstens, R., Vandeplassche, L., 2009. Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut 58, 357–365. Tack, J., Vos, R., Janssens, J., Salter, J., Jauffret, S., Vandeplassche, G., 2003. Influence of tegaserod on proximal gastric tone and on the perception of gastric distension. Aliment. Pharmacol. Ther. 18, 1031–1037. Takaki, M., Goto, K., Kawahara, I., 2014. The 5-hydroxytryptamine 4 receptor agonistinduced actions and enteric neurogenesis in the gut. J. Neurogastroenterol. Motil. 20, 17–30. Tanaka, K.F., Samuels, B.A., Hen, R., 2012. Serotonin receptor expression along the dorsal-ventral axis of mouse hippocampus. Phil. Trans. R. Soc. Lond. Ser. B Biol. Sci. 367, 2395–2401. Tatsumi, M., Groshan, K., Blakely, R.D., Richelson, E., 1997. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur. J. Pharmacol. 340, 249–258. Taylor, C.A., Jung, H.Y., 1998. Disorders of mood after traumatic brain injury. Semin. Clin. Neuropsychiatry 3, 224–231. Teixeira, C.M., Rosen, Z.B., Suri, D., Sun, Q., Hersh, M., Sargin, D., Dincheva, I., Morgan, A.A., Spivack, S., Krok, A.C., Hirschfeld-Stoler, T., Lambe, E.K., Siegelbaum, S.A., Ansorge, M.S., 2018. Hippocampal 5-HT input regulates memory formation and schaffer collateral excitation. Neuron 98, 992–1004 e1004. Terry Jr., A.V., Buccafusco, J.J., Jackson, W.J., Prendergast, M.A., Fontana, D.J., Wong, E.H.F., Bonhaus, D.W., Weller, P., Eglen, R.M., 1998. Enhanced delayed matching performance in younger and older macaques administered the 5-HT4 receptor agonist, RS17017. Psychopharmacology 135, 407–415.

Portincasa, P., Mearin, F., Robert, M., Plazas, M.J., Mas, M., Heras, J., 2009. Efficacy and tolerability of cinitapride in the treatment of functional dyspepsia and delayed gastric emptying. Gastroenterol. Hepatol. 32, 669–676. Posserud, I., Agerforz, P., Ekman, R., Bjornsson, E.S., Abrahamsson, H., Simren, M., 2004. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress. Gut 53, 1102–1108. Prather, C.M., Camilleri, M., Zinsmeister, A.R., McKinzie, S., Thomforde, G., 2000. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 118, 463–468. Privitera, G., Misenheimer, M., Doraiswamy, P.M., 2013. From weight loss to weight gain: appetite changes in major depressive disorder as a mirror into brain-environment interactions. Front. Psychol. 4. Pullar, I.A., Boot, J.R., Broadmore, R.J., Eyre, T.A., Cooper, J., Sanger, G.J., Wedley, S., Mitchell, S.N., 2004. The role of the 5-HT1D receptor as a presynaptic autoreceptor in the Guinea pig. Eur. J. Pharmacol. 493, 85–93. Qin, H.Y., Cheng, C.W., Tang, X.D., Bian, Z.X., 2014. Impact of psychological stress on irritable bowel syndrome. World J. Gastroenterol. 20, 14126–14131. Quigley, E.M., 2012. Prucalopride: safety, efficacy and potential applications. Ther. Adv. Gastroenterol. 5, 23–30. Quigley, E.M., 2015. Prokinetics in the management of functional gastrointestinal disorders. J. Neurogastroenterol. Motil. 21, 330–336. Quigley, E.M., Vandeplassche, L., Kerstens, R., Ausma, J., 2009. Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation - a 12-week, randomized, double-blind, placebo-controlled study. Aliment. Pharmacol. Ther. 29, 315–328. Ramadan, N.M., Skljarevski, V., Phebus, L.A., Johnson, K.W., 2003. 5-HT1F receptor agonists in acute migraine treatment: a hypothesis. Cephalalgia 23, 776–785. Ramírez, M.J., 2013. 5-HT6 receptors and Alzheimer's disease. Alzheimer's Res. Ther. 5 15-15. Rao, M., Gershon, M.D., 2016. The bowel and beyond: the enteric nervous system in neurological disorders. Nat. Rev. Gastroenterol. Hepatol. 13, 517–528. Rao, M., Gershon, M.D., 2017. Neurogastroenterology: the dynamic cycle of life in the enteric nervous system. Nat. Rev. Gastroenterol. Hepatol. 14, 453–454. Raote, I., Bhattacharya, A., Panicker, M., 2007. Serotonin 2A (5-HT2A) receptor function: ligand-dependent mechanisms and pathways. In: Raote, I., Bhattacharya, A., Panicker, M.M. (Eds.), Frontiers in Neuroscience, Serotonin Receptors in Neurobiology. CRC Press/Taylor & Francis, pp. 1–44. Rapport, M.M., 1949. Serum vasoconstrictor (serotonin) the presence of creatinine in the complex; a proposed structure of the vasoconstrictor principle. J. Biol. Chem. 180, 961–969. Rausch, J.L., Johnson, M.E., Corley, K.M., Hobby, H.M., Shendarkar, N., Fei, Y., Ganapathy, V., Leibach, F.H., 2003. Depressed patients have higher body temperature: 5-HT transporter long promoter region effects. Neuropsychobiology 47, 120–127. Ray, A.M., Kelsell, R.E., Houp, J.A., Kelly, F.M., Medhurst, A.D., Cox, H.M., Calver, A.R., 2009. Identification of a novel 5-HT4 receptor splice variant (r5-HT4c1) and preliminary characterisation of specific 5-HT4a and 5-HT4b receptor antibodies. Eur. J. Pharmacol. 604, 1–11. Rebholz, H., Friedman, E., Castello, J., 2018. Alterations of expression of the serotonin 5HT4 receptor in brain disorders. Int. J. Mol. Sci. 19, E3581. Reynolds, G.P., Mason, S.L., Meldrum, A., De Keczer, S., Parties, H., Eglen, R.M., Wong, E.H.F., 1995. 5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases. Br. J. Pharmacol. 114, 993–998. Richardson-Jones, J.W., Craige, C.P., Guiard, B.P., Stephen, A., Metzger, K.L., Kung, H.F., Gardier, A.M., Dranovsky, A., David, D.J., Beck, S.G., Hen, R., Leonardo, E.D., 2010. 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron 65, 40–52. Rosel, P., Arranz, B., Urretavizcaya, M., Oros, M., San, L., Navarro, M.A., 2004. Altered 5HT2A and 5-HT4 postsynaptic receptors and their intracellular signalling systems IP3 and cAMP in brains from depressed violent suicide victims. Neuropsychobiology 49, 189–195. Ross, S.B., Renyi, A.L., 1969. Inhibition of the uptake of tritiated 5-hydroxytryptamine in brain tissue. Eur. J. Pharmacol. 7, 270–277. Rubio-Guerra, A.F., Rodriguez-Lopez, L., Vargas-Ayala, G., Huerta-Ramirez, S., Serna, D.C., Lozano-Nuevo, J.J., 2013. Depression increases the risk for uncontrolled hypertension. Exp. Clin. Cardiol. 18, 10–12. Sagami, Y., Shimada, Y., Tayama, J., Nomura, T., Satake, M., Endo, Y., Shoji, T., Karahashi, K., Hongo, M., Fukudo, S., 2004. Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome. Gut 53, 958–964. Sakurai, K., Nagahara, A., Inoue, K., Akiyama, J., Mabe, K., Suzuki, J., Habu, Y., Araki, A., Suzuki, T., Satoh, K., Nagami, H., Harada, R., Tano, N., Kusaka, M., Fujioka, Y., Fujimura, T., Shigeto, N., Oumi, T., Miwa, J., Miwa, H., Fujimoto, K., Kinoshita, Y., Haruma, K., 2012. Efficacy of omeprazole, famotidine, mosapride and teprenone in patients with upper gastrointestinal symptoms: an omeprazole-controlled randomized study (J-FOCUS). BMC Gastroenterol. 12, 42. Sanders, N.M., Wilkinson, C.W., Taborsky Jr., G.J., Al-Noori, S., Daumen, W., Zavosh, A., Figlewicz, D.P., 2008. The selective serotonin reuptake inhibitor sertraline enhances counterregulatory responses to hypoglycemia. Am. J. Physiol. Endocrinol. Metabol. 294, E853–E860. Sanger, G., 1987. Increased gut cholinergic activity and antagonism of 5‐hydroxytryptamine M‐receptors by BRL 24924: potential clinical importance of BRL 24924. Br. J. Pharmacol. 91, 77–87. Sanger, G.J., Quigley, E.M.M., 2010. Constipation, IBs and the 5-HT4 Receptor: what role for prucalopride? Clin. Med. Gastroenterol. 3, S4136 CGast.

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Neuropharmacology 166 (2020) 107969

L. Agrawal, et al.

Vilaró, M.T., Doménech, T., Palacios, J.M., Mengod, G., 2002. Cloning and characterization of a novel human 5-HT4 receptor variant that lacks the alternatively spliced carboxy terminal exon. RT-PCR distribution in human brain and periphery of multiple 5-HT4 receptor variants. Neuropharmacology 42, 60–73. WHO, 2018. Mental Disorders Affect One in Four People. World Health Organisation, Geneva. Walther, D.J., Peter, J.U., Bashammakh, S., Hortnagl, H., Voits, M., Fink, H., Bader, M., 2003. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299, 76. Weissman, M.M., Leaf, P.J., Bruce, M.L., Florio, L., 1988. The epidemiology of dysthymia in five communities: rates, risks, comorbidity, and treatment. Am. J. Psychiatry 145, 815–819. Wohlfarth, C., Schmitteckert, S., Härtle, J.D., Houghton, L.A., Dweep, H., Fortea, M., Assadi, G., Braun, A., Mederer, T., Pöhner, S., Becker, P.P., Fischer, C., Granzow, M., Mönnikes, H., Mayer, E.A., Sayuk, G., Boeckxstaens, G., Wouters, M.M., Simrén, M., Lindberg, G., Ohlsson, B., Schmidt, P.T., Dlugosz, A., Agreus, L., Andreasson, A., D'Amato, M., Burwinkel, B., Bermejo, J.L., Röth, R., Lasitschka, F., Vicario, M., Metzger, M., Santos, J., Rappold, G.A., Martinez, C., Niesler, B., 2017. miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome. Sci. Rep. 7, 14680. Woods, S., Clarke, N.N., Layfield, R., Fone, K.C.F., 2012. 5-HT(6) receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms. Br. J. Pharmacol. 167, 436–449. Wu, J.C., 2012. Psychological Co-morbidity in functional gastrointestinal disorders: epidemiology, mechanisms and management. J. Neurogastroenterol. Motil. 18, 13–18. Yang, D.C., Goldstin, B., Moormann, A.E., Flynn, D.L., Gullikson, G.W., 1993. SC-53606, a potent and selective antagonist of 5-hydroxytryptamine4 receptors in isolated rat esophageal tunica muscularis mucosae. J. Pharmacol. Exp. Ther. 266, 1339–1347. Yang, L., Zhao, Y., Wang, Y., Liu, L., Zhang, X., Li, B., Cui, R., 2015. The effects of psychological stress on depression. Curr. Neuropharmacol. 13, 494–504. Yohn, C.N., Gergues, M.M., Samuels, B.A., 2017. The role of 5-HT receptors in depression. Mol. Brain 10 28-28. Yoshida, H., Kanamaru, C., Ohtani, A., Li, F., Senzaki, K., Shiga, T., 2011. Subtype specific roles of serotonin receptors in the spine formation of cortical neurons in vitro. Neurosci. Res. 71, 311–314. Zhang, A.Z., Wang, Q.C., Huang, K.M., Huang, J.G., Zhou, C.H., Sun, F.Q., Wang, S.W., Wu, F.T., 2016. Prevalence of depression and anxiety in patients with chronic digestive system diseases: a multicenter epidemiological study. World J. Gastroenterol. 22, 9437–9444. Zhang, X., Gainetdinov, R.R., Beaulieu, J.M., Sotnikova, T.D., Burch, L.H., Williams, R.B., Schwartz, D.A., Krishnan, K.R., Caron, M.G., 2005. Loss of function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16.

Thomas, D.R., 2006. 5-ht5A receptors as a therapeutic target. Pharmacol. Ther. 111, 707–714. Thompson, A.J., Lummis, S.C.R., 2006. 5-HT3 receptors. Curr. Pharmaceut. Des. 12, 3615–3630. Tichomirowa, M.A., Keck, M.E., Schneider, H.J., Paez-Pereda, M., Renner, U., Holsboer, F., Stalla, G.K., 2005. Endocrine disturbances in depression. J. Endocrinol. Investig. 28, 89–99. Tjurmina, O.A., Armando, I., Saavedra, J.M., Goldstein, D.S., Murphy, D.L., 2002. Exaggerated adrenomedullary response to immobilization in mice with targeted disruption of the serotonin transporter gene. Endocrinology 143, 4520–4526. Tong, W., Kamiyama, Y., Ridolfi, T.J., Zietlow, A., Zheng, J., Kosinski, L., Ludwig, K., Takahashi, T., 2011. The role of 5-HT3 and 5-HT4 receptors in the adaptive mechanism of colonic transit following the parasympathetic denervation in rats. J. Surg. Res. 171, 510–516. Track, N.S., 1980. The gastrointestinal endocrine system. Can. Med. Assoc. J. 122, 287–292. Tsuchida, Y., Hatao, F., Fujisawa, M., Murata, T., Kaminishi, M., Seto, Y., Hori, M., Ozaki, H., 2011. Neuronal stimulation with 5-hydroxytryptamine 4 receptor induces antiinflammatory actions via α7nACh receptors on muscularis macrophages associated with postoperative ileus. Gut 60, 638–647. Tuladhar, B.R., Ge, L., Naylor, R.J., 2003. 5-HT7 receptors mediate the inhibitory effect of 5-HT on peristalsis in the isolated Guinea-pig ileum. Br. J. Pharmacol. 138, 1210–1214. Tuladhar, B.R., Womack, M.D., Naylor, R.J., 2000. Pharmacological characterization of the 5-HT receptor-mediated contraction in the mouse isolated ileum. Br. J. Pharmacol. 131, 1716–1722. Udenfriend, S., Weissbach, H., Clark, C.T., 1955. The extimation of 5-hydroxytryptamine (serotonin) in biological tissues. J. Biol. Chem. 215, 337–344. Upadhyay, S.N., 2003. Serotonin receptors, agonists and antagonists. Indian J. Nucl. Med. 18, 1–11. Van de Kar, L.D., Javed, A., Zhang, Y., Serres, F., Raap, D.K., Gray, T.S., 2001. 5-HT2A receptors stimulate ACTH, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic CRF and oxytocin-expressing cells. J. Neurosci. 21, 3572. Van Praag, H.M., 1978. Amine hypotheses of affective disorders. In: Iversen, L.L., Iversen, S.D., Snyder, S.H. (Eds.), Handbook of Psychopharmacology: Volume 13 Biology of Mood and Antianxiety Drugs. Springer US, Boston, MA, pp. 187–297. Veysey, M.J., Malcolm, P., Mallet, A.I., Jenkins, P.J., Besser, G.M., Murphy, G.M., Dowling, R.H., 2001. Effects of cisapride on gall bladder emptying, intestinal transit, and serum deoxycholate: a prospective, randomised, double blind, placebo controlled trial. Gut 49, 828. Vilaró, M.T., Cortés, R., Mengod, G., 2005. Serotonin 5-HT4 receptors and their mRNAs in rat and Guinea pig brain: distribution and effects of neurotoxic lesions. J. Comp. Neurol. 484, 418–439.

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