# The Serotonin 4 Receptor Subtype: A Target of Particular Interest, Especially for Brain Disorders

Véronique Sgambato

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Véronique Sgambato. The Serotonin 4 Receptor Subtype: A Target of Particular Interest, Especially for Brain Disorders. International Journal of Molecular Sciences, 2024, 25 (10), pp.5245. 10.3390/ijms25105245. [https://doi.org/10.3390/ijms25105245]

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# The Serotonin 4 Receptor Subtype: A Target of Particular Interest, Especially for Brain Disorders

Véronique Sgambato <fnref n="1" />,<fnref n="2" /> ID

**Abstract:** In recent years, particular attention has been paid to the serotonin 4 receptor, which is well expressed in the brain, but also peripherally in various organs. The cerebral distribution of this receptor is well conserved across species, with high densities in the basal ganglia, where they are expressed by GABAergic neurons. The 5-HT₄ receptor is also present in the cerebral cortex, hippocampus, and amygdala, where they are carried by glutamatergic or cholinergic neurons. Outside the central nervous system, the 5-HT₄ receptor is notably expressed in the gastrointestinal tract. The wide distribution of the 5-HT₄ receptor undoubtedly contributes to its involvement in a plethora of functions. In addition, the modulation of this receptor influences the release of serotonin, but also the release of other neurotransmitters such as acetylcholine and dopamine. This is a considerable asset, as the modulation of the 5-HT₄ receptor can therefore play a direct or indirect beneficial role in various disorders. One of the main advantages of this receptor is that it mediates a much faster antidepressant and anxiolytic action than classical selective serotonin reuptake inhibitors. Another major benefit of the 5-HT₄ receptor is that its activation enhances cognitive performance, probably via the release of acetylcholine. The expression of the 5-HT₄ receptor is also altered in various eating disorders, and its activation by the 5-HT₄ agonist negatively regulates food intake. Additionally, although the cerebral expression of this receptor is modified in certain movement-related disorders, it is still yet to be determined whether this receptor plays a key role in their pathophysiology. Finally, there is no longer any need to demonstrate the value of 5-HT₄ receptor agonists in the pharmacological management of gastrointestinal disorders.

**Keywords:** serotonin; 5-HT₄ receptor; depression; anxiety; cognitive decline; movement disorders; eating disorders; constipation

## 1. Introduction

Serotonin (5-HT, 5-hydroxytryptamine) is a monoamine synthesized from an essential amino acid, L-tryptophan. L-tryptophan can cross the blood-brain barrier and be converted by the enzyme tryptophan hydroxylase 2 (TPH2) into L-5-hydroxytryptophan. The latter is then converted to 5-HT after decarboxylation by aromatic amino acid decarboxylase (AADC). TPH2 is specific to serotonergic neurons in the central nervous system and is responsible for 5-HT synthesis in the brain [1,2], while AADC is localized in many cell types. In the brain, the majority of the cell bodies of serotonin-containing neurons are located in the brain stem and grouped into nine nuclei (named B1 to B9) which are, in turn, divided into the rostral or superior group and the caudal or inferior group [3,4]. The rostral group is located in the pons and midbrain and consists of both the dorsal nucleus (DRN) and medial nucleus (MRN) of the raphe [5,6]. The caudal group is located in the medulla and consists of nuclei projecting mainly to the spinal cord [5]. Although, in many brain territories, projections from serotonergic neurons originate from both the DRN and MRN, in some regions, 5-HT innervation originates solely or preferentially from the DRN or MRN. This is the case, for example, of the hippocampus, the dorsal part of which receives serotonergic

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**Citation:** Sgambato, V. The Serotonin 4 Receptor Subtype: A Target of Particular Interest, Especially for Brain Disorders. *Int. J. Mol. Sci.* **2024**, *25*, 5245. https://doi.org/10.3390/ijms25105245

Academic Editor: Elena
E. Voronezhskaya

Received: 15 March 2024

Revised: 22 April 2024

Accepted: 7 May 2024

Published: 11 May 2024

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<footnote n="1">¹ Institut des Sciences Cognitives Marc Jeannerod (ISCMJ), Unité Mixte de Recherche 5229 du Centre National de la Recherche Scientifique (CNRS), 69675 Bron, France; veronique.sgambato@inserm.fr; Tel.: +33-4379-11249</footnote>

<footnote n="2">² UFR Biosciences, Université de Lyon 1, 69100 Villeurbanne, France</footnote>
innervation from the MRN [7]. On the other hand, the 5-HT fibers of the striatum, globus pallidus, lateral septum, and amygdala, including the prefrontal cortex, come from the DRN [8]. Along with the MRN, the DRN innervates the ventral part of the hippocampus and the prefrontal cortex [8] and certain nuclei of the thalamus [7,9,10]. There are also dense serotonergic projections between the DRN and MRN [11]. The central nervous system therefore contains a small number of 5-HT neurons grouped together in nuclei, but these neurons release serotonin diffusely throughout the brain at chemical synapses or by volume transmission [4,12]. Serotonin can therefore exert a modulating action on a wide variety of neuronal circuits and therefore functions [13,14]. The action of serotonin is complicated by the identification of seven families of serotonin receptor subtypes (5-HT₁ to 5-HT₇ receptors) in the brain [15]. Six of these are metabotropic G-protein-coupled receptors and one (the 5-HT₃ receptor) is a ligand-gated ion channel (ionotropic receptor) [16]. This leads to the existence of eighteen 5-HT receptor subtypes plus a number of isoforms resulting from alternative mRNA splicing [17]. While all 5-HT receptor subtypes have post-synaptic expression on target cells, some subtypes, such as 5-HT₁A, 5-HT₁B/D, and 5-HT₂B, are also localized pre-synaptically on the 5-HT neurons themselves (autoreceptors). Finally, 5-HT receptors also differ in their brain expression profiles in the brain [18] and in their interactions with other neurotransmitter systems.

In recent years, particular attention has been focused on the serotonin 4 receptor sub-
type [19–21], originally identified and cloned in rodents [22,23]. This receptor is positively
coupled to adenylate cyclase via a Gs-type G protein leading to the canonical activation
of the cAMP/PKA pathway [24]. But activation of the 5-HT₄ receptor can also lead to
the activation of the ERK signaling pathway independently of G proteins [25]. In ad-
dition to the fact that the 5-HT₄ receptor has a constitutive activity, which is expressed
at low receptor levels, another important feature of the receptor is that it can establish
homodimers or heterodimers with several other proteins. These dimers functionally im-
pact the signaling pathways on which they act [26]. In the brain, the 5-HT₄ receptor is
mainly located on neurons and has a dual somatodendritic and axonal localization [27].
Its cerebral distribution is highly conserved across species [27,28] with the highest den-
sities in basal ganglia, particularly in the striatum [29,30] and the substantia nigra [31].
The 5-HT₄ receptor is expressed by GABAergic neurons, as neurotoxic lesions of rodent
basal ganglia components lead to dramatic decreases in 5-HT₄ receptor binding in these
regions [27,32]. The post-synaptic expression of the 5-HT₄ receptor seems independent of
dopaminergic neurons, as a dopaminergic lesion induced by intranigral injection of the
6-hydroxydopamine in rodents does not induce decreases in its expression in the striatum
or the substantia nigra [27,32]. Similarly, the lesion of serotonergic neurons by intra-raphe
injection of the 5,7-dihydroxytryptamine upregulates the 5-HT₄ receptor binding in the
basal ganglia and hippocampal regions [32]. The 5-HT₄ receptor is also highly expressed in
the cerebral cortex, hippocampus, and amygdala, where it may be carried by glutamatergic
or cholinergic neurons, depending on the region [33,34]. The distribution of this receptor
has also been studied in the post-mortem human brain by in situ hybridization and ligand
binding studies and has been found to be high in basal ganglia regions and moderate to
low in hippocampal formation and the cortical mantle [28]. Substantial evidence from
preclinical and clinical studies have indicated an inverse relationship between the central
5-HT tonus and the density of the 5-HT₄ receptor. In animals, 5-HT depletion or 5-HT
boosting by the use of antidepressants, or again serotonin transporter gene manipulation,
all lead to alterations of the 5-HT₄ receptor binding in the brain [35–37]. In humans, the
polymorphism of the serotonin transporter also results in different 5-HT levels and to
different expression levels of the 5-HT₄ receptor [38]. And as it has been demonstrated that
the density of the 5-HT₄ receptor adapts to the variations in brain extracellular 5-HT levels
induced by antidepressant treatment, the central 5-HT₄ receptor binding is now used as an
in vivo biomarker of serotonergic tonus [39]. Outside the central nervous system, the 5-HT₄
receptor is known to be also expressed in the gastrointestinal tract, the cardiovascular
system, the bladder, and the adrenal glands [40].
The 5-HT₄ receptor is involved in several functions. It mediates a positive feedback effect on the 5-HT neurons themselves. Indeed, the 5-HT₄ receptor in the prefrontal cortex has a positive influence on the rate of discharge of 5-HT neurons in the raphe and increases the probability of action potential emissions via the positive feedback loop from the prefrontal cortex to the dorsal raphe [41,42]. The administration of 5-HT₄ agonists also activates raphe 5-HT neurons [41,43]. It also releases 5-HT in the hippocampus [44]. The action of 5-HT₄ receptors in the hippocampus plays an important role in the regulation of synaptic plasticity and related memory mechanisms [45]. Apart from the serotonergic system, the modulation of the 5-HT₄ receptor has effects on the homeostasis of other neurotransmitter systems such as acetylcholine or dopamine [46]. The stimulation of the 5-HT₄ receptor facilitates the release of acetylcholine in the frontal cortex of awake rats [47]. Similarly, the 5-HT₄ receptor has been shown to facilitate dopamine release in the rat striatum both in vitro and in vivo [48]. The fact that modulation of the 5-HT₄ receptor can affect the release of different neurotransmitters highlights the importance of this receptor as a potential therapeutic player in a variety of pathological conditions.

## 1.1. Mood and Anxiety Disorders

One of the major interests of this receptor is its potential involvement in mood and anxiety disorders (Table 1). It has already been shown that the 5-HT₄ receptor expression is altered in various rodent models of depression. Some studies have reported a decrease in 5-HT₄ receptor expression [35,49], while others have observed an increase [50]. It is highly probable that these divergent results are due to the use of different animal models of depression. On the contrary, similar results were obtained by studies modulating 5-HT₄ receptor activation. Drugs that activate the 5-HT₄ receptor play a fast-acting beneficial role on behavioral markers of depression or anxiety [51]. Electrophysiological, molecular, morphological, and behavioral changes that have previously been specifically linked to beneficial long-term treatment with selective serotonin reuptake inhibitors are already present after only 3 days of treatment when using 5-HT₄ agonists in rodents [52]. The lack of 5-HT₄ receptor modulates mood-like disorders [53] and further impacts the response to antidepressants in rodents [54]. Overexpression of the 5-HT₄ receptor in the medial prefrontal cortex leads to antidepressant effects [55], whereas its functional ablation throughout the brain [54] or only in the hippocampus [53] causes anxiety and mood disorders. The pharmacological modulation of the 5-HT₄ receptor located in the lateral habenula also produces antidepressant effects, via changes in monoamine levels in the prefrontal cortex and hippocampus in parkinsonian rats [56]. Yet, links have been shown between the antidepressant action of 5-HT₄ receptor agonists and mechanisms of synaptic plasticity or gene regulation in the hippocampus. For example, the administration of 5-HT₄ receptor agonists leads to the upregulation of mRNAs encoding BDNF (brain-derived neurotrophic factor) in the hippocampus. This increase results from activation of the CREB (cAMP-response element-binding protein) signaling pathway, which stimulates the expression of various neurotrophic factors in the hippocampus, including BDNF [57]. Furthermore, it has been shown that the stimulation of the 5-HT₄ receptor drives neurogenesis in the hippocampus, while the lack of or the antagonism toward the 5-HT₄ receptor reduces these effects [58–61]. Furthermore, it has been shown that the activation of the 5-HT₄ receptor boosts the formation and the function of dendritic spines [62,63] and more generally acts as a unique modulator of synaptic plasticity mechanisms in the hippocampus [64].

In support of these preclinical data, several human studies have also shown that expression levels of the 5-HT₄ receptor are altered in mood disorders and/or depression (Table 1). Autopsy results of brain tissue from antidepressant-free, violent suicide victims have shown a high density of the 5-HT₄ receptor in the frontal cortex and caudate nucleus compared with control subjects [65]. In vivo PET (positron emission tomography) data have shown a lower cerebral 5-HT₄ receptor binding in patients with major depressive disorder than in healthy subjects [66,67]. And concomitant anxiety in patients suffering from depression is also negatively associated with 5-HT₄ receptor brain binding [68]. There
is also an association between brain 5-HT₄ receptor binding and reactivity to emotional faces in depressed and healthy individuals: the higher the concomitant anxiety, the lower the binding in the brain [69]. The global brain binding of this receptor has also been positively linked to high trait aggression in men [70]. Finally, a polymorphism in the 5-HT₄ receptor in its C-terminal region has been linked to unipolar depression in humans [71], suggesting that genomic variations of this gene may confer susceptibility to mood disorders. A more recent study aimed to assess the association of the 5-HT₄ receptor polymorphism (rs1345697) with depressive symptom improvement after 6 months of antidepressant treatment and found that there is an impact of this rs1345697 polymorphism on the improvement in depressive symptoms and remission of these symptoms after antidepressant treatment [72]. Taken together, these preclinical and clinical data tend to show that there is rather a drop in expression of the 5-HT₄ receptor associated with mood and anxiety disorders, and that the use of agonists of this receptor could reduce them.

## 1.2. Cognitive Disorders

Another attraction of the 5-HT₄ receptor subtype is that its activation can improve learning and memory (Table 2). Several preclinical experimental paradigms have evidenced such pro-cognitive properties [73,74]. Significant and reproducible improvements in a delayed matching to sample task accuracy are observed following an oral administration of a 5-HT₄ agonist in both younger and older monkeys [73]. In rodents, activation of the 5-HT₄ receptor leads to an increase in acetylcholine release, which counteracts memory deficits [21,46]. And it has been shown that the 5-HT₄ receptor plays a specific and unique role in modulating the long-term potentiation of synapses in the hippocampus [75] and thus the memory mechanisms dependent on this structure [64]. It also promotes here the maturation of neuronal dendritic spines [63]. In humans, PET imaging studies have shown an inverse relationship between brain 5-HT₄ receptor binding and memory performance in healthy subjects [76,77]. Even weaker brain binding is associated with memory dysfunction in untreated depressive patients compared with healthy individuals [67]. Finally, as in animals, stimulation of the 5-HT₄ receptor by prucalopride improves cognitive performance in healthy subjects [78,79]. This beneficial effect is achieved by enhancing the resting-state functional connectivity between regions involved in cognitive networks while reducing that of the default mode network [80].
<table><caption>**Table 1.** List and main characteristics of preclinical and clinical studies involving the 5-HT₄ receptor in mood and anxiety disorders.</caption><thead><tr><th>Goal of the Study</th><th>Methods of 5-HT<sub>4</sub> Receptor Investigation</th><th>Models</th><th>Main Results</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="5">5-HT<sub>4</sub> receptor polymorphism</td><td rowspan="2">Polymorphism</td><td>Bipolar or depressed individuals</td><td>C-terminal region linked to mood disorders *</td><td>[71]</td></tr><tr><td>Major depressed individuals</td><td>Genotype GG of rs1345697 polymorphism associated with lower remission rates</td><td>[72]</td></tr><tr><td rowspan="2">Binding assays</td><td rowspan="2">Violent suicide human victims</td><td>↑</td><td>in frontal cortex *</td><td rowspan="2">[65]</td></tr><tr><td>↑</td><td>in caudate nucleus *</td></tr><tr><td rowspan="4">Autoradiography</td><td rowspan="2">Rat depression model</td><td>↓</td><td>in the hippocampus</td><td rowspan="2">[35]</td></tr><tr><td>↓</td><td>in hippocampus and basal ganglia under chronic paroxetine</td></tr><tr><td rowspan="2">Mouse depression models</td><td>↓</td><td>in hippocampus, hypothalamus, and lateral globus pallidus after 5-HT depletion</td><td rowspan="2">[50]</td></tr><tr><td>↑</td><td>in ventral hippocampus</td></tr><tr><td rowspan="10">5-HT<sub>4</sub> receptor expression</td><td rowspan="2">Deletion</td><td rowspan="2">KO mouse</td><td>↑</td><td>in caudal caudate putamen</td><td rowspan="2">[50]</td></tr><tr><td>↓</td><td>Attenuation of "dematuration" of hippocampal granule cells</td></tr><tr><td rowspan="2">qRT-PCR, Western blot</td><td rowspan="2">Rat depression models</td><td>↓</td><td>Anxiety and anhedonia induced and responses to antidepressant impacted</td><td>[54]</td></tr><tr><td>↓</td><td>in hippocampus associated with anhedonia</td><td>[49]</td></tr><tr><td>qRT-PCR</td><td>Casein kinase 2 KO mouse</td><td>↑</td><td>in prefrontal cortex associated with anti-depressant-like phenotype</td><td>[55]</td></tr><tr><td>In situ hybridization</td><td>KO mouse</td><td>↑</td><td>Fluoxetine-induced neurogenesis abolished</td><td>[61]</td></tr><tr><td>Overexpression</td><td>Mouse</td><td>↑</td><td>Anti-depressant-like phenotype</td><td>[55]</td></tr><tr><td rowspan="3">PET imaging</td><td rowspan="2">Healthy individuals</td><td>↓</td><td>in striatum and limbic regions negatively correlated with number of first-degree relatives treated for major depression</td><td>[66]</td></tr><tr><td>↓</td><td>Positive correlation with high trait aggression, only in males</td><td>[70]</td></tr><tr><td>Anxious and depressed individuals</td><td>↓</td><td>in global brain</td><td>[68]</td></tr><tr><td rowspan="2">Depressed individuals</td><td rowspan="2">Depressed individuals</td><td>↓</td><td>Negative correlation with concomitant anxiety *</td><td>[69]</td></tr><tr><td>↓</td><td>in global brain *</td><td>[67]</td></tr></tbody></table>
<table><caption>**Table 1. Cont.**</caption><thead><tr><th>Goal of the Study</th><th>Methods of 5-HT<sub>4</sub> Receptor Investigation</th><th>Models</th><th>Main Results</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="4">5-HT<sub>4</sub> receptor modulation</td><td rowspan="4">5-HT<sub>4</sub> receptor agonist</td><td>Rat depression models</td><td>Depressive-like behavioral responses</td><td>[52]</td></tr><tr><td>Rat</td><td>Depressive- and anxiety-like behavioral responses</td><td>[57]</td></tr><tr><td>Rat model of Parkinson's disease</td><td>Depressive-like behavioral responses</td><td>[56]</td></tr><tr><td>KO mouse</td><td>Antidepressant behavioral responses</td><td>[53]</td></tr></tbody></table>

<table><caption>**Table 2.** List and main characteristics of preclinical and clinical studies involving the 5-HT₄ receptor in cognitive disorders.</caption><thead><tr><th>Goal of the Study</th><th>Methods of 5-HT<sub>4</sub> Receptor Investigation</th><th>Models</th><th>Main Results</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="4">5-HT<sub>4</sub> receptor expression</td><td rowspan="3">PET imaging</td><td>Subjects with early Alzheimer's disease</td><td>In global brain and positively correlated with beta-amyloid accumulation</td><td>[81]</td></tr><tr><td>Healthy young adult individuals</td><td>Inverse relationship with memory performance</td><td>[76]</td></tr><tr><td>Depressed patients</td><td>Inverse relationship with positive and neutral word recall performance</td><td>[77]</td></tr><tr><td>Western blot</td><td>Rat model of Parkinson's disease</td><td>in global brain * associated with memory dysfunction</td><td>[67]</td></tr><tr><td rowspan="10">5-HT<sub>4</sub> receptor modulation</td><td rowspan="8">5-HT<sub>4</sub> receptor agonist</td><td>Macaque young and old)</td><td>Learning improved</td><td>[73]</td></tr><tr><td>Mouse</td><td>Memory improved</td><td>[74]</td></tr><tr><td>Mouse model of scopolamine-induced deficit</td><td>Memory deficits counteracted</td><td>[46]</td></tr><tr><td>Mouse model of Parkinson's disease</td><td>Restored facilitation of contextual fear extinction</td><td>[83]</td></tr><tr><td>Rat model of Parkinson's disease</td><td>Working memory improved</td><td>[82]</td></tr><tr><td>Rat model of Alzheimer's disease</td><td>Memory deficits and associated mechanisms counteracted</td><td>[84]</td></tr><tr><td>Healthy young adult individuals</td><td>Pro-cognitive effects induced</td><td>[78]</td></tr><tr><td>5-HT<sub>4</sub> receptor agonist and antagonist</td><td>ePet1-cre; Ai32 mouse</td><td>Mnesic performance improved associated with increased hippocampal activity</td><td>[79]</td></tr><tr><td></td><td></td><td>Memory formation modulated</td><td>[75]</td></tr></tbody></table>

<footnote>* in comparison with healthy individuals. Up arrows indicate an increase, down arrows a decrease.</footnote>

<footnote>* in comparison with healthy individuals. Up arrows indicate an increase, down arrow indicates a decrease.</footnote>
Stimulation of 5-HT₄ receptors is also proving promising in various pathological situations. In a rat model of Alzheimer's disease, the administration of a 5-HT₄ receptor agonist improves cognitive performance via a reduction in apoptotic neurons and an improvement in synaptic function in the hippocampus [84]. In humans with early Alzheimer's disease, a PET study elegantly showed that there is an increase in brain 5-HT₄ receptor binding (parietal cortex, lateral prefrontal cortex, lateral temporal cortex, posterior cingulate gyrus, and hippocampus), and that this global cerebral upregulation is positively correlated with the cortical detection of beta-amyloid accumulation [81]. These preclinical and clinical data indicate that upregulation of the 5-HT₄ receptor in the brain is beneficial, particularly in the hippocampus, where 5-HT₄ receptor stimulation favors synaptic plasticity and memory mechanisms. This also suggests that increased expression of this receptor is a compensatory mechanism designed not only to counteract the accumulation of amyloid plaques [85], but also to promote acetylcholine release [47] and improve cognition.

Pro-cognitive effects are also mediated by 5-HT₄ receptors in Parkinson's neurodegenerative disease and may be underpinned by similar mechanisms. Indeed, the systemic administration of a 5-HT₄ agonist improves the facilitation of contextual fear extinction, although without affecting hippocampal 5-HT₄ receptors at the mRNA level, in the parkinsonian mice [83]. But another study on the parkinsonian rat has shown that lesioning the dopaminergic neurons of the median forebrain bundle produces cognitive deficits which are associated with a hippocampal increase in the receptor protein expression. Moreover, the local modulation of this receptor can counteract the memory deficits displayed by the animal, notably via increases in dopamine and serotonin in the hippocampus and the amygdala [82]. This suggests that, once again, the increased expression of the 5-HT₄ receptor is a compensatory mechanism that stimulates the release of other neurotransmitters, thereby counteracting memory deficits.

Taken together, these data indicate that the stimulation of 5-HT₄ receptors triggers a number of possible mechanisms (release of acetylcholine, serotonin, or dopamine; stimulation of maturation and synaptic plasticity in the hippocampus; induction of mechanisms able to counteract the accumulation of toxic aggregates and neuronal apoptosis), aimed at improving cognitive impairments. They also strengthen the view that 5-HT₄ receptor agonists could be used in humans under different conditions: in subjects without a neurodegenerative pathology to improve memory deficits, and in elderly subjects affected by several evolutive diseases involving severe cognitive impairment [86].

### 1.3. *Movement Disorders*

Few studies have addressed the question of whether the 5-HT₄ receptor subtype is in any way involved in movement disorders (Table 3). However, some animal models exist for inducing motor deficits or complications, in which either the impact of the pharmacological modulation of this receptor or its potential alteration of expression has been analyzed. In a rat model of morphine-driven stereotyped behavior and haloperidol-induced catalepsy, the systemic pharmacological blockade of the 5-HT₄ receptor has no impact, suggesting that 5-HT₄ receptor antagonism does not modulate motor behaviors related to the change in dopamine transmission [87]. Similarly, the turning behavior induced by amphetamine in unilateral dopamine-denervated rats is not affected after antagonizing the 5-HT₄ receptor [88]. Divergent results were obtained in the parkinsonian mice. One study showed that the administration of 5-HT₄ receptor agonists did not improve motor impairment [83]. On the contrary, a 7-day administration of prucalopride, a 5-HT₄ agonist, induced a beneficial effect on motor deficits (bradykinesia, exploration, balance, and muscle strength) in the parkinsonian mice, by attenuating the striatal loss of dopamine [89]. Studies that have simply analyzed variations in receptor expression without using pharmacological ligands show divergent results. Changes in the striatal expression of the 5-HT₄ receptor are not observed after dopaminergic lesion induction, nor after a chronic levodopa treatment, leading to abnormal involuntary movements (i.e., dyskinesias) in a rat model of Parkinson's disease [90]. By contrast, using in vivo PET imaging and immunohistochemistry
on post-mortem tissue, we found that the 5-HT₄ receptor is upregulated in the striatum of parkinsonian macaques and rats, and further increased following chronic levodopa treatment, inducing dyskinesias in both animal species [91]. In humans, binding studies have not revealed any significant differences in 5-HT₄ receptor expression in the putamen or the substantia nigra between control subjects and Parkinson's sufferers, although there is a tendency for this receptor to increase in the putamen of patients [92,93]. By contrast, in Huntington's patients, who exhibit involuntary movements, a marked putaminal decrease in the 5-HT₄ receptor density is found [92]. However, a 3-week treatment with mosapride, a 5-HT₄ receptor agonist, improved motor functions in a small number of Parkinsonian patients [94]. Taken together, these results show that the question of possible links between altered 5-HT₄ receptor expression in the brain and movement disorders remains a largely open question. Further studies are sorely needed to elucidate whether or not this 5-HT₄ receptor plays a role in the pathophysiology of movement disorders.

<table><caption>**Table 3.** List and main characteristics of preclinical and clinical studies involving the 5-HT₄ receptor in movement disorders.</caption><thead><tr><th>Goal of the Study</th><th>Methods of 5-HT<sub>4</sub> Receptor Investigation</th><th>Models</th><th>Main Results</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="4">5-HT<sub>4</sub> receptor expression</td><td rowspan="2">Binding assays</td><td>Patients affected by Huntington's disease</td><td>↓</td><td>in putamen *</td><td>[92,93]</td></tr><tr><td>Patients affected by Parkinson's disease</td><td>↔</td><td>in putamen and nigra *</td><td>[92,93]</td></tr><tr><td>In situ hybridization</td><td>Rat model of Parkinson's disease</td><td>↔</td><td>in striatum</td><td>[90]</td></tr><tr><td>PET imaging immunohistochemistry</td><td></td><td>↑</td><td>in motor striatum</td><td>[91]</td></tr><tr><td rowspan="4">5-HT<sub>6</sub> receptor modulation</td><td rowspan="2">5-HT<sub>4</sub> receptor agonist</td><td>Patients affected by Parkinson's disease</td><td>Motor functions improved</td><td>[94]</td></tr><tr><td>Mouse model of Parkinson's disease</td><td>No motor improvement<br>Motor deficits improved associated with rescued striatal dopamine levels</td><td>[83]<br>[89]</td></tr><tr><td>5-HT<sub>4</sub> receptor antagonist</td><td>Rat model of amphetamine-induced turning behavior</td><td>No impact</td><td>[88]</td></tr></tbody></table>

### 1.4. Food Disorders

Several studies, first in rodents and non-human primates, then in humans, have shown that the 5-HT₄ receptor is associated with the control of food intake (Table 4). In normal or food-deprived mice, the local stimulation of the 5-HT₄ receptor in the nucleus accumbens, a region involved in the reward system, inhibits food intake, an effect that is not obtained in 5-HT₄-receptor-deficient mice [95]. The same group has also shown that deletion or overexpression of the 5-HT₄ receptor in the medial prefrontal cortex induces overeating or hypophagia, respectively [96]. In obese rats, there is a higher level of the accumbal 5-HT₄ receptor, whose stimulation with an agonist reduces eating [97]. In normal macaque monkeys, here again, the modulation of this receptor reduces or enhances the motivation for food intake, following systemic administration of a 5-HT₄ receptor agonist or antagonist, respectively (personal communications). Similarly, in dopamine-lesioned macaques, the local injection of a 5-HT₄ agonist into the ventral striatum (the rodent equivalent of the nucleus accumbens) triggers a reduced motivation for food intake (personal communications). In humans, a PET imaging study found that obesity

<footnote>* in comparison with healthy individuals. Up arrow indicates an increase, down arrow a decrease. Horizontal arrows indicate no change.</footnote>
is associated with the greater availability of this receptor in the nucleus accumbens and ventral pallidum of the brain reward circuit [98]. All these preclinical and clinical data point in the same direction and show that the high expression of 5-HT₄ receptors in the nucleus accumbens is associated with a high body mass index, and that the stimulation of 5-HT₄ receptors helps reduce the food intake.

<table><caption>**Table 4.** List and main characteristics of preclinical and clinical studies involving the 5-HT₄ receptor in food disorders.</caption><thead><tr><th>Goal of the Study</th><th>Methods of 5-HT<sub>4</sub> Receptor Investigation</th><th>Models</th><th>Main Results</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="5">5-HT<sub>4</sub> receptor expression</td><td>Autoradiography</td><td>Rat model of obesity</td><td>↑</td><td>In nucleus accumbens</td><td>[97]</td></tr><tr><td>PET imaging</td><td>Normal to high body mass index individuals</td><td>↑</td><td>In nucleus accumbens, ventral pallidum, left hippocampus, and orbitofrontal cortex, associated with obesity</td><td>[98]</td></tr><tr><td>Deletion</td><td>Mouse</td><td>↑</td><td>Food intake</td><td>[96]</td></tr><tr><td>Overexpression</td><td>Mouse</td><td>↓</td><td>Food intake</td><td>[96]</td></tr><tr><td>Food intake modulated</td><td>KO mouse</td><td>↓</td><td>Food intake</td><td>[96]</td></tr><tr><td rowspan="3">5-HT<sub>4</sub> receptor modulation</td><td rowspan="2">5-HT<sub>4</sub> receptor agonist or antagonist</td><td>Mouse</td><td>Food intake modulated</td><td>[95]</td></tr><tr><td>Macaque</td><td>Modulated food intake</td><td>personal communications</td></tr><tr><td>5-HT<sub>4</sub> receptor agonist</td><td>Macaque model of Parkinson's disease</td><td>↓</td><td>Food intake</td><td>personal communications</td></tr></tbody></table>

Up arrows indicate an increase, down arrows a decrease.

## 1.5. Other Brain Disorders

Finally, one clinical study has reported an association between the methylation of the 5-HT₄ receptor promoter and autism spectrum disorder [99]. Another has linked hippocampal structural changes in psychosis to the distribution of the 5-HT₄ receptor [100], opening new avenues of research on this receptor. More recently, a study investigating the possible involvement of the serotonergic system in the pathophysiology of amyotrophic lateral sclerosis showed, using a transgenic mouse model, that systemic administration of a 5-HT₄ receptor antagonist worsened the disease's phenotype. It degraded motor function, without affecting disease progression. However, the 5-HT₄ receptor antagonist also induced an increase in the expression of proteins forming abnormal aggregates, as well as an increase in the number of glial cells at the expense of neurons, in these mice [101], suggesting that using 5-HT₄ receptors agonists might be of particular interest.

## 1.6. Gastrointestinal Disorders

Interestingly also, the 5-HT₄ receptor agonists have been evaluated as prokinetics in the gastrointestinal tract (Table 5). The gavage of prucalopride causes faster whole gut transit and colonic motility and these effects are blocked by a 5-HT₄ receptor antagonist and are not detected in 5-HT₄ receptor knockout mice [102]. Sacral nerve electrical stimulation can improve defecation and accelerate the recovery of colonic transmission functions in a rat model of constipation, and these effects involve an upregulation of the 5-HT₄ receptor in the colon [103]. The 5-HT₄ receptor agonists prucalopride and tegaserod have both been approved by the FDA (Food and Drug Administration) and are used to
treat various gastrointestinal-related conditions, including nausea, diarrhea, gastroparesis, constipation, and pain in irritable bowel syndrome [104]. In patients suffering from chronic idiopathic constipation [104], prucalopride is highly efficient, and other highly selective 5-HT₄ receptor agonists are still in advanced development [105]. In other pathologies, such as Parkinson's disease, 5-HT₄ receptor agonists can also improve non-motor symptoms such as constipation. This has been demonstrated both preclinically and clinically. Rats with bilateral lesions of nigral dopaminergic neurons exhibit a reduced 5-HT₄ receptor expression in the colonic muscular layer and manifest constipation, which is counteracted by a 5-HT₄ receptor agonist (cisapride) [106]. In the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice, a beneficial effect is obtained on the integrity of the intestinal barrier after intraperitoneal administration of prucalopride, the 5-HT₄ receptor agonist, for 7 days [89]. Clinical studies have also tested the effects of the pharmacological stimulation of the 5-HT₄ receptor on constipation in Parkinson's disease (see [107]) (Table 5). It has been shown that administration of the 5-HT₄ receptor agonist mosapride for 3 months improves the intestinal transit in patients without worsening their parkinsonian symptoms or causing serious side-effects [108]. Another study involving a small number of parkinsonian patients showed an increasing gastric motility during mosapride treatment [94]. These data are interesting insofar as constipation is a non-motor symptom that may precede the onset of motor symptoms in Parkinson's disease. We could therefore imagine that the therapeutic targeting of the 5-HT₄ receptor could be modulated according to the symptom (motor or non-motor), but also according to the stage of the pathology (early, advanced, or late).

<table><caption>**Table 5.** List and main characteristics of preclinical and clinical studies involving the 5-HT₄ receptor in gastrointestinal disorders.</caption><thead><tr><th>Goal of the Study</th><th>Methods of 5-HT<sub>4</sub> Receptor Investigation</th><th>Models</th><th>Main Results</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="2">5-HT<sub>4</sub> receptor expression</td><td>ELISA, qRT-PCR, immunohistochemistry, Western blot</td><td>Rat model of constipation</td><td>↑ In colon after sacral nerve electrical stimulation</td><td>[103]</td></tr><tr><td>Western blot</td><td>Rat model of Parkinson's disease</td><td>↓ In colon, associated with constipation</td><td>[106]</td></tr><tr><td rowspan="5">5-HT<sub>4</sub> receptor modulation</td><td rowspan="2">5-HT<sub>4</sub> receptor agonist</td><td>Patients affected by Parkinson's disease</td><td>↑ Intestinal transit</td><td>[108]</td></tr><tr><td>Rat model of Parkinson's disease</td><td>↑ Gastric motility</td><td>[94]</td></tr><tr><td rowspan="2">5-HT<sub>4</sub> receptor agonist and antagonist</td><td>Rat model of Parkinson's disease</td><td>↑ In colon<br>↓ Constipation</td><td>[106]</td></tr><tr><td>Mouse model of Parkinson's disease</td><td>Beneficial effect on intestinal barrier integrity</td><td>[89]</td></tr><tr><td>5-HT<sub>4</sub> receptor agonist and antagonist</td><td>Naïve or KO mouse</td><td>Modulated gut transit and colonic motility</td><td>[102]</td></tr></tbody></table>

Up arrows indicate an increase, down arrows a decrease.

## 2. Conclusions

All these studies, both preclinical and clinical, highlight this 5-HT₄ receptor as a potential therapeutic target, especially for various brain disorders. While the benefits of activating this receptor have been well demonstrated at the preclinical level for certain conditions, such as depressive symptoms, memory deficits, food consumption, and constipation, there is still some way to go in terms of the interest in acting pharmacologically on this receptor in the field of movement disorders. In humans, the activation of this
receptor to counteract certain disorders is promising but remains to be validated, since only gastrointestinal disorders can be improved so far by using compounds acting toward this receptor. Further studies are sorely needed to unravel all the mysteries surrounding this receptor, both in terms of its functions and its potential therapeutic use.

**Funding:** Writing this review article was supported by the Fondation de France and the Agence Nationale de la Recherche. V.S. is supported by INSERM (Institut National de la Santé et de la Recherche Médicale).

**Conflicts of Interest:** The author declares no conflict of interest.

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