Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

5-Hydroxytryptamine Receptor 6

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101490


Historical Background

Up to date, there are 14 different subtypes of 5-HT receptors (5-HTR) discovered and they are divided into seven major classes (5-HT1 to 5-HT7). All these receptors are G protein-coupled receptors (GPCRs), except for 5-HT3 that is a part of the Cys-loop superfamily of ligand-gated ion channels (LGICs). 5-HT1 class (composed by 5 subtypes – 5-HT1a-f) is coupled with a Gi/o protein, which inhibits adenylate cyclase (AC) activity and modulates calcium and potassium channels; 5-HT2 class (composed by 3 subtypes – 5-HT2a-c) is coupled with a Gq protein, which activates the phospholipase C pathways and releases inositol triphosphate (IP3) and diacylglycerol (DAG). The last group is composed by 5-HT4 to 5HT7 receptors and they are all Gs coupled; therefore, their activation regulates positively the function of AC (Marazziti et al. 2013).

5-HT6 was first found in NCB-20 cells in 1979 by MacDermont and coworkers, but its pharmacological features remained unclear. More detailed studies began to appear in 1993 when the 5-HT6 receptor was cloned (Monsma et al. 1993). But only in 1994 Unsworth and Molinoff suggested the creation of the sixth serotoninergic receptor subtype based on their studies in N18TG2 cells (Unsworth and Molinoff 1994). This suggestion was based on the contradictory function observed in the cell receptors where their binding and pharmacological profile did not match any previous known subtype of serotonin receptor. 5-HT6 are different from all other 5-HT receptors; they are formed by a short third cytoplasmatic loop and a long C-terminal tail and include one intron situated in the middle of the third cytoplasmatic loop (Marazziti et al. 2013).

The studies related to 5-HT6 are still scarce and the mechanisms of action related to the activation of this receptor not completely elucidated (Pereira et al. 2015), but it started to draw special attention in recent years because of its involvement in learning and memory and since some antidepressants and antipsychotics have a high affinity for it (Schechter et al. 2008; Karila et al. 2015; Pereira et al. 2015). 5-HT6 receptors are found mostly in the central nervous system (CNS) and are predominantly expressed in the striatum, limbic system, and cortex and so far only one nonselective radio ligand for PET imaging of the 5-HT6 receptor has made its way into humans, namely, [11C] GSK215083 (3-[(3-fl uorophenyl)sulfonyl]- 8-(4-[11C]methyl-1-piperazinyl) quinolone (Knudsen and Hasselbalch 2014). Some 5-HT6 receptor ligands are already in clinical trial, but several new and more effective ones still need to go through preclinical trials. It seems that 5-HT6 modulation can be a useful new future target to the treatment of memory deficit in dementia and schizophrenia, obesity, drug abuse control, depression, and anxiety.


The gene of this receptor is located in chromosome 1p35.p36 and encodes for a 438-aminoacid protein that shows less than 50% sequence homology with the other 5-HT receptor isoforms and it is a seven transmembrane-spanning protein (Hirst et al. 2003) (Fig. 1). Between the other 5-HT receptors, 5-HT2a is the one that presents more similarities with 5-HT6 (Karila et al. 2015). This gene is well conserved between humans and rats, showing 89% homology and similar brain distribution (Monsma et al. 1993; Ruat et al. 1993). On the other hand the distribution and concentration in mice are not so remarkably similar, making rats the first choice in preclinical studies of 5-HT6 activity (Hirst et al. 2003), even if mice have 97% homology with rat and 89% with humans. The differences between rats and mice are due to the substitution of few aminoacids, within the binding pocket: one on ECL2 (extracellular loop 2), one on TM5, and two on TM6 (transmembrane 5 and 6) (Karila et al. 2015).
5-Hydroxytryptamine Receptor 6, Fig. 1

Schematic representation of the seven transmembrane domains and the long C-terminal of 5-HT6 receptor structure

5-HT6 is mostly located in the CNS, with very low expression levels in the peripheral tissues, suggesting low peripheral effects after activation and deactivation of the receptor (Monsma et al. 1993; Ruat et al. 1993; Karila et al. 2015). These receptors are heteroreceptors in 5-HT cell bodies and terminals and as well cholinergic neurons relative to GABAergic and glutamatergic neurons (Helboe et al. 2015; Karila et al. 2015).

Based on immunolocalization, northern blotting, in situ hybridization, and autoradiography binding studies, the 5-HT6 receptor is highly concentrated in striatum, olfactory tuberculous, nucleus accumbens, hippocampus, cortex, cerebellum, hypothalamus, and the amygdala, with similar distribution between humans and rats. (Monsma et al. 1993; Ruat et al. 1993; Hirst et al. 2003). On the other hand, related to mice, Hirst et al. (2003) pointed a lower expression of this receptor in the basal ganglia of the mouse, unlike humans and rats. Furthermore, site-directed mutagenesis experiments showed that caution is needed when predicting clinical effects of 5-HT6 modulation in mice once the binding pocket where antagonists and agonists bind is quite different in the mouse receptor compared with human or rat 5-HT6 receptor subtypes.

The first research in 5–HT6 ligand bind site was performed in rats and cites the presence of 4 residues forming the site: Trp102, Asp106, 126 Ala287, and Asn290. And the first analysis of this receptor, previous to 2000, believed that only Asn290 was mutated when comparing mouse and rat. These works pointed that in the mouse Asn290 is a Ser290 (serine). Posterior work performed by Hirst et al. (2003) identifies changes in two more residues; according to them, the agonist/antagonist affinity differences are due to a Ser290 and Ser277 in TM6, a Ser175 in ECL2, and a Tyr188 in TM5 (Fig. 2).
5-Hydroxytryptamine Receptor 6, Fig. 2

Schematic representation of the structural differences between 5-HT6R in rat and mouse (sites of mutation in yellow)

Molecular Mechanisms

As mentioned in the start of this chapter, 5-HT6, together with 5-HT4, 5-HT5, and 5-HT7 are coupled to Gs, i.e., the activation of these receptors will activate Gs and therefore regulates positively the function of adenylate cyclase (AC) (Di Chiara et al. 2011; Marazziti et al. 2013; Karila et al. 2015). AC activation leads to activation of cyclic adenosine monophosphate (cAMP) that will increase protein kinase A (PKA) activation and therefore phosphorylation of cAMP response element-binding protein (CREB) and extracellular signal-regulated kinases (ERK) phosphorylation. According to Di Chiara et al. (2011), the 5-HT6 receptor also interacts with two other proteins: Fyn-kinase and Jab1 (also known as the fifth component of the CSN complex, CSN5). Fyn presents tyrosine kinase activity and 5-HT6R binds to the SH3 of Fyn via its carboxyl terminal and induces autophosphorylation of the Tyr-420 and therefore activation of Fyn. This is the cascade that it is believed to activate ERK1/2 (Di Chiara et al. 2011; Karila et al. 2015), one of the mechanisms of action that it is believed to be related to the pro-cognitive functions of 5-HT6 (Pereira et al. 2015) (Fig. 3). Di Chiara also mentions that Fyn and 5-HT6R (5-HT6 receptor) have a reciprocal function, where activation of the serotoninergic receptor facilitates translocation of Fyn to the cytoplasm and Fyn expression increases 5-HT6R expression. In other hand, decrease of Jab1 would promote decrease of 5-HT6 receptor expression, while 5-HT6R promotes translocation of Jab1 to the nucleus and increased c-Jun phosphorylation (Di Chiara et al. 2011). Recently, other interactions of 5-HT6R were reported, according to Karila et al. (2015), another function that was found is that it interacts with the mammalian target of rapamycin (mTOR) and the cognitive deficits present in schizophrenia would be related to a high activation of mTOR in prefrontal cortex via activation of 5-HT6R; therefore, it’s antagonism would prevent action of mTOR and consequently improve memory. Agonism of 5-HT6R could as well constitutively interact with cyclin-dependent kinase 5 (CdK5 plays some pivotal roles in the central nervous system including higher cognitive functions such as learning and memory formation) and promote neurite growth (Karila et al. 2015).
5-Hydroxytryptamine Receptor 6, Fig. 3

Schematic representation of the 5-HT6 receptor molecular pathways activation. cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; CREB: cAMP response element-binding protein; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinases; Fyn: proto-oncogene tyrosine-protein kinase Fyn ; Jab1: c-Jun activation domain-binding protein-1 ; K+: potassium; mTOR: mammalian target of rapamycin; CdK5: cyclin-dependent kinase 5

Finally, it is also important to mention that the activity of 5-HT6R also regulates the release of other neurotransmitters, like acetylcholine, norepinephrine, gamma-aminobutyric acid (GABA), and glutamate. 5-HT6R antagonism seems to be related to increased extracellular levels of acetylcholine, glutamate, and norepinephrine in several brain regions, while 5-HT6R agonism was reported to decrease corticostriatal levels of glutamate through GABA activation (Schechter et al. 2008; Karila et al. 2015). According to Schechter et al. (2008), the administration of a 5-HT6 agonist increased the level of GABA extracellularly without altering the levels of glutamate and norepinephrine, as well as there was a modest, but significant, decrease in cortical dopamine levels. Schechter also reported a robust increase in the levels of GABA in the dorsal hippocampus, striatum, and amygdala, but no changes in nucleus accumbens or thalamus.

5-HT6 and Psychiatric Disorders

Some 5-HT6 receptor ligands entered the clinical development as potential antipsychotics and antidementia agents, and other potential therapeutic applications have also been suggested, as for example antidepressant, antiobesity drugs, and drug abuse control (Heal et al. 2008; Marazziti et al. 2013; Karila et al. 2015; Pereira et al. 2015).

5-HT6 Polymorphism

Small changes in the gene sequence can bring significant detriment to its function. Some detrimental changes had been reported in the serotoninergic system and correlated to psychiatric disorders, for example, one of the most reported changes is the short allele version of SERT (serotonin transporter) and depression. Related to 5-HT6 less is known and therefore few polymorphisms reported. Tsai et al. (1999) were the first to report such a polymorphism; they determined that the 267C allele of the 5-HT6 receptor is a significant risk factor for Alzheimer’s disease in a study with 92 AD patients and 104 controls in a Chinese population, but failed in a posterior study when they tried to correlated the same allele with depression prevalence in the AD patients. As well, no correlation was observed between the 267T allele (silent RsaI restriction fragment length polymorphism) and depression or mood disorder in another study conducted in the Chinese population, but this polymorphism was correlated to increased risk of schizophrenia and lower risk of development of Parkinson disease (PD) (Messina et al. 2002). In conclusion, some studies had pointed out a polymorphism in 5-HT6 been related to disorders with a strong cognitive impairment phenotype, but the significance of these findings remains to be established since they have not always been replicated.

5-HT6 and Memory and Cognition

The most researched area in 5-HT6 receptor activity is memory. Special attention is given to the effects of the 5-HT6R antagonism to the treatment of memory impairment in Alzheimer disease, since 5-HT6 antagonists increase the levels of extracellular acetylcholine. Also, shortly after the discovery of 5-HT6 receptors, Roth et al. (1994) reported that a large number of typical and atypical antipsychotic drugs bound with high affinity to 5-HT6 receptors.

Since 5-HT6 receptors are abundant in the hippocampus, nucleus accumbens, and striatum, it was expected that the modulation of these receptors would have effects in learning and memory and it is indeed the fact for both agonists and antagonists of 5-HT6 (Schechter et al. 2008). Selective 5-HT6 receptor antagonists produce pro-cognitive effects in several learning and memory paradigms, while 5-HT6 receptor agonists had present contradictory results.

The pro-cognitive effects of 5-HT6 antagonism are currently investigated in clinical trials in Alzheimer (AD) patients (Codony et al. 2011; Woods et al. 2012; Knudsen and Hasselbalch 2014). Studies point out that 5HT6 antagonism improved the cognitive function of patients with AD and also that in the postmortem AD brains show a reduction of this receptor in frontal as well as temporal cortical areas (Knudsen and Hasselbalch 2014). Moreover, 5-HT6 receptors have been demonstrated to regulate central cholinergic and glutamatergic neurotransmission (Woods et al. 2012). Several 5-HT6R antagonists were effective in increasing the discrimination index in the novel object recognition test as well as improving retention in the water maze, although they failed to improve acquisition of spatial learning (Codony et al. 2011). According to Woods et al. (2012), both agonism (with E6801) and antagonism (with EMD386088) of 5-HT6 receptors were capable to revert emotional memory impairment induced by cholinergic and glutamatergic antagonism showing a therapeutic potential of 5-HT6 receptor compounds in the treatment of cognitive dysfunction, such as seen in Alzheimer’s disease and schizophrenia. In their study, rats were conditioned to pair an unavoidable foot shock with a light and a tone during the training phase; after these experiences, every time the animal was exposed to the same environment, the context would produce a freezing behavior. But pretreatment with a cholinergic or glutamatergic antagonist (scopolamine and MK-801, respectively) impaired the freezing behavior and in their work, both agonism and antagonism of 5-HT6 was capable to reverse the memory impairment caused by cholinergic and glutamatergic antagonism.

Di Chiara et al. (2011) reported that antagonism of 5-HT6 receptors reverse the cognitive impairment caused by repeated exposure to phencyclidine (PCP), as does typical and atypical antipsychotics. They also mention that antipsychotics that block in addition to D2, the 5-HT6, and 5-HT2a might exert beneficial effects on the cognitive deficit in schizophrenia.

5-HT6 in Weight

For the last 15 years, the number of obese people has increased significantly, starting to make obesity to be considered a global epidemic problem. According to healthcare experts, obesity will be one of the leading causes of morbidity and mortality for this and future generations (Heal et al. 2008); therefore, not only diet but pharmacological intervention is needed as well and it is important to research new drugs that do not cause addiction in the users, as the dopamine agonists amphetamine (and derived drugs that are the most common appetite inhibitor).

The first study to report the roll of 5-HT6 in weight and feeding was Woolley et al. (2001). The focus of this study was to evaluate the effects of 5HT6 inhibition in memory, using two approaches: 5-HT6 antagonist administration (Ro046790) and intracerebroventricular (ICV) administration of an antisense oligonucleotide complementary to 5HT6. The result observed in weight was that 5HT6 inhibition induced weight loss and reduced food intake.

In 2006, another group corroborates the results using a highly selective 5HT6 agonist (E6837) and monitoring body weight, food and water intake, and plasma indices of comorbid risk factor. Interesting here, as it happens in memory, both agonism and antagonism of 5HT6 show similar effects. According to Heal and coworkers, up to 2008, 5HT6 target was not used in the clinic. But also according to them, based on the 5-HT6 distribution and the preclinical finds with agonists and antagonists, it is a potential target to the treatment of obesity and metabolic syndrome. Heal and coworkers reported that the use of drugs that modulated 5HT6 activity produced not only weight loss but as well changed some important markers of obesity, as visceral adiposity and insulin resistance; moreover, they mention that the effects of 5HT6 ligands indicate that they reduce food intake by enhancing satiety (meal termination) rather than reducing appetite (meal initiation), been therefore better than the current anorectic available drugs. According to Heal et al. (2008), the high distribution of 5-HT6 in olfactory tubercle, cortex, nucleus accumbens, striatum, hippocampus, cerebellum, thalamus, substantia nigra, superficial layer of the superior colliculus, motor trigeminal nucleus, and facial nucleus and in the hypothalamus, which are brain region related to food intake and energy expenditure, points to the important roll of 5-HT6 in energy consumption, food intake, and satiety.

5-HT6 in Depression and Anxiety

Both agonists and antagonists of 5-HT6 seem to have the same effect in depression and anxiety and the mechanisms involved in such effect are not elucidate yet (Di Chiara et al. 2011; Karila et al. 2015). Most of the works showed a positive effect of 5-HT6 agonism and antagonism in depression using forced swim test (FST) and tail suspension test. Related to anxiety, agonism and antagonism of 5-HT6 showed effect in Vogel conflicts, elevated plus maze test, defensive burying, and polydipsia. Interestingly, some of the composts were effective in both depression and anxiety and their effects were reverse by administration of 5-HT6 antagonist, reinforce the importance of conduct more studies of the antidepressant and anxiolytic effects of 5-HT6 to a possible new candidate to treat anxio-depressive disorders (Karila et al. 2015). Also Karila et al. (2015) pointed out that 5-HT6 is involved in the control of sleep, and alterations in sleep-wake pattern are a common comorbid in both, depression and anxiety.

Pereira et al. (2015) observed an effect of acute treatment with a 5-HT6 agonist in the FST and as well a memory improvement in the same treatment schedule. They also observed an increase in the levels of phosphorylated ERK and BDNF, showing a pro-cognitive and antidepressant effect of 5-HT6 stimulation.

According to Schechter et al. (2008), agonism of 5-HT6 decreased the drinking behavior in a model of schedule-induced polydipsia (a model used to study obsessive compulsive disorder – OCD). Pereira et al. (2015), in other hand, failed to show any anxiolytic effect of 5-HT6 agonism, but such difference can be due to the fact that they used different animals (rats versus mice) or the nature of the test itself, since Pereira used elevated plus maze, a test sensitive to generalized anxiety, while Schechter observed an effect in OCD.

5-HT6 in Drug Abuse

Drug addiction is one of the most serious and complex psychiatric disorders, specially due to the fact that it do not affect just the individual user but all aspects of social and professional/economic life. Even after all this years of research in addiction, few is known about the neurobiologia of addiction, but it seems to be a malfunction of the brain hedonic tone regulation and motivational system (Müller et al. 2010). Most types of drug addiction can be ameliorated by treatment with some sort of serotoninergic drug.

Few studies had been done related to the 5-HT6 receptor: Related to cocaine some studies showed that 5-HT6 antagonism inhibit cocaine induce conditional place preference (CPP); related to amphetamine, a study reported that 5-HT6 antagonism enhanced discriminative stimulus properties; 5-HT6 antagonism potentiates the discriminative and locomotor effects of nicotine; and finally, 5-HT6 antagonism decrease the seeking for nicotine and ethanol. According to Bruin et al. (2013), the antagonism of 5-HT6 could control drug abuse; in this paper, the administration of the antagonist CPM42 decreased the nicotine self-administration and reinstatement of nicotine seeking and as well reinstatement of ethanol seeking in rats trained to self-administration in the 5-choice serial reaction time task (5-CSRTT).

It is crucial to point out though that few studies or none were performed related to different drugs of abuse, for example, up to date no studies were performed to evaluate the possible role of 5-HT6 in methamphetamine, MDMA, morphine and therefore it is fundamental to research the possible role of this serotoninergic receptor in addiction.


In summary, 5-HT6 is a receptor highly expressed in areas related to cognition and therefore present a high potential as future treatment to cognitive impairment for several psychiatric disorders. This effect is specially remarkable to Alzheimer, since one of the secondary effects of 5-HT6 stimulation is the increase of acetylcholine. Modulation of 5-HT6 function might be a good target to the treatment of anxio-depressive disorder and as well obesity and drug addiction. Therefore, more studies to better understand the mechanisms of action and molecular pathways related to agonism and antagonism of 5-HT6 are needed.



Author financial support: CAPES (Coordination for the Improvement of Higher Education Personnel).


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Clinical Neuroscience, Center of Molecular Medicine L801Karolinska Institutet - Karolinska University HospitalStockholmSweden