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Current Medicinal Chemistry, 2011, 18, ????-???? 1
0929-8673/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.
Serotonin Receptors of Type 6 (5-HT6): What can we Expect from them?
D. Marazziti*,1, S. Baroni1, M. Catena Dell’Osso1, F. Bordi2 and F. Borsini2
1Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Pisa, Italy
2Sigma-tau Industrie Farmaceutiche Riunite s.p.a., Pomezia, Italy
Abstract: The serotonin (5-HT) receptors of type 6 (5-HT6) are relatively new. They are quite different from all other 5-HT receptors, as
they are characterized by a short third cytoplasmatic loop and a long C-terminal tail, and contain one intron located in the middle of the
third cytoplasmatic loop. After some initial controversies, the available findings are now apparently more congruent. Nevertheless,
discrepancies still exist, such as those in binding affinity, effects of 5-HT6 ligands on brain catecholamines and behavioral syndromes
mediated by them. Much interest in 5-HT6 receptors was triggered by the evidence that some antipsychotics could bind to them.
Subsequently, despite the lack of complete information on metabolic patterns of the various compounds, some of 5-HT6 receptor ligands
entered the clinical development as potential anti-dementia, antipsychotic and anti-obese drugs. In any case, the available information on
the pharmacology of 5-HT6 receptors is still quite scant. Therefore, with the present paper we aimed at reporting a comprehensive review
on the status of art of the 5-HT6 receptors, while highlighting the potential clinical applications of 5-HT6 receptor agonists/antagonists.
Keywords: Serotonin, serotonin receptors, serotonin receptors of type 6, agonists, antagonists, neurochemistry, pharmacology.
INTRODUCTION
Serotonin (5-HT) is a neurotransmitter involved in a variety of
physiological functions including appetite, sleep, memory and
learning, sexuality, and in several psychopathological disorders,
such as depression, anxiety, obsessive-compulsive disorders,
schizophrenia [1, 2]. The physiological functions of 5-HT are
mediated by the interaction with multiple receptors. Up-to now,
seven major families of 5-HT receptors have been identified (5-
HT1–5-HT7), comprising a total of 14 distinct receptor subtypes [3].
The 5-HT6 receptors are amongst the latest 5-HT receptors
identified. They belong to the family of G protein-coupled
receptors, but are quite different from all other 5-HT receptors, as
they are characterized by a short third cytoplasmatic loop and a
long C-terminal tail, and contain one intron located in the middle of
the third cytoplasmatic loop [4]. After some initial controversies,
the available findings are now apparently more congruent.
Nevertheless, discrepancies still exist, such as those in binding
affinity, effects of 5-HT6 ligands on brain catecholamines and
behavioral syndromes which may be mediated by them.
A great bulk of interest in 5-HT6 receptors was triggered by the
evidence that some antidepressants and several antipsychotics
behave as antagonists at their level [4, 5]. In particular, 5-HT6
receptors show a high affinity for both typical antipsychotics, such
as chlorpromazine and amoxapine, as well as atypical ones, in
particular clozapine and olanzapine [6-8]. Furthermore, 5-HT6
receptors have been shown to influence acetylcholine release in the
frontal cortex [9], so that it has been hypothesized that they may
play a role in cognition deficits and in some forms of anxiety
disorders [4].
For this reason, despite the lack of complete information on the
metabolic pattern of the various compounds, some 5-HT6 receptor
ligands entered the clinical development as potential anti-dementia
agents [10-16], antipsychotics [12] and anti-obese drugs [17].
The aim of the present paper was to offer a comprehensive
review on the available data on 5-HT6 receptors, with a special
emphasis on the future and potential clinical use of 5-HT6 receptors
agonists/antagonists.
THE HISTORY OF 5HT6 RECEPTORS
The history of 5-HT6 receptors started with the finding of a
possible 5-HT receptor in NCB-20 cells, a clonal cell line formed
*Address correspondence to this author at the Dipartimento di Psichiatria,
Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Via Roma 67, 56100
Pisa, Italy; Tel: +390502219768; Fax: +390502219787;
E-mail: dmarazzi@psico.med.unipi.it
by a hybrid of mouse neuroblastoma N18TG2 and Chinese hamster
18-day embryonic brain explant [18-21]. However, the
pharmacological characteristics of this receptor were ambiguous,
for example, the binding of 5-HT was increased or reduced by the
non-hydrolyzable GTP analog, Gpp(NH)p [18, 19]. Furthermore,
Conner and Mansour (1990) [20] reported that LSD behaved as a
potent partial agonist in the adenylate cyclase assay, but did not
displace the bound [3H]5-HT. In contrast, 8-OHDPAT, a 5-HT1A/7
agonist, displaced the [3H]5-HT binding, but had no effect on
cAMP. When ascorbic acid was used to stabilize 5-HT to the
putative receptor, no specific binding of [3H]5-HT was detected.
Therefore, the binding studies produced results that did not
correspond to the potencies obtained with the 5-HT-activated
cyclase assay. In 1994, Usworth and Molinoff interpreted the
previous data as characteristics of both the 5-HT1C and 5-HT4
subtypes, and for these reasons, they it could not be attributable to
any known 5-HT receptor. These authors, thus, suggested that the
neuroblastoma N18TG2 cells presented a 5-HT receptor subtype
with 5-HT6 pharmacological characteristics [22].
The results began to be definitively more consistent when the 5-
HT6 receptor was cloned in 1993 [6, 23]. The cloning was carried
out with PCR amplification by using cDNA prepared from rat
striatal mRNA (St-B17). The receptor was radiolabelled with
[125I]LSD, [3H]LSD or [3H]5-HT in COS-7 or HEK cells, whose
binding sites were unaffected by the presence of guanine
nucleotides [6], while suggesting, therefore, recognition of the low
affinity, uncoupled state of the receptor.
A few years later, some frame shift errors were described in the
gene sequence cloned previously [6, 23, 24], but the affinity values
of different compounds for 5-HT6 receptors seemed quite similar,
with the exclusion of metergoline (Ki = 400 nM in Kohen et al.,
1996; Ki = 30 nM in Monsma et al., 1993).
Boess et al. (1997) published interesting results on cloned rat
HEK-293 cells, and showed that better binding values of 5-HT6
receptors could be obtained at low temperatures, that [3H]LSD and
[3H]5-HT may differently interact with 5-HT6 receptors and that
LSD behaved as a partial agonist at that level [25]. However, the
affinity values of compounds for the 5-HT6 receptors did not seem
to be always congruent, for instance, the Ki value of lisuride,
ranged between 30 nM [25], and 1.3 nM [26].
More agreement exists on the evidence that 5-HT receptors in
mice have different brain distribution and pharmacological
characteristics, as compared with rats and humans [27]. In fact,
LSD, unlike rat and human 5-HT6 receptors [20, 25], behaves as a
full agonist in mice [28]. In addition, no specific binding of the
selective radioligand [125I]SB258585 to 5-HT6 receptors was
2 Current Medicinal Chemistry, 2011 Vol. 18, No. 1 Marazziti et al.
observed in mouse brain [29, 30] and 5-HT6 receptor mRNA levels
were extremely low in mouse brain [29]. Finally, the ligand Ro04-
6790, which binds to rat and human 5-HT6 receptors, failed to do so
in cloned mouse 5-HT6 receptors [29].
However, a 4.2 kb band for 5-HT6 receptor mRNA was
observed in whole mouse brain [30], similarly to that found in rats
and humans (see next paragraph), and 5-HT6 receptor mRNA
expression by RT-PCR was measured in prefrontal cortex,
hypothalamus, hippocampus and midbrain of mice [31]. A non-
functional variant of a human 5-HT6 receptor variant was found in
humans, but not in mice or rats [32].
5-HT6: mRNA AND RECEPTOR DISTRIBUTION
The 5-HT6 mRNA distribution was evaluated by Northern blot
analysis of poly(A)+ RNA encoding St-B17 prepared from a variety
of rat brain regions and peripheral tissues [6]. A single transcript of
about 4.2 kb was observed in different rat regions. In contrast to
previous results, two transcripts of 4.1 and 3.2 kb were found in the
brain [23]. The Northern blot analysis of guinea pig revealed a
single transcript of about 3.8 kb, mainly concentrated in the
striatum and olfactory tubercles. The 5-HT6 cDNA probe
hybridized to two mRNAs of about 4 and 3.2 kb in length in human
tissues [24].
In rats, a wide agreement exists that the mRNA for 5-HT6
receptors is present in certain brain areas, such as the striatum,
cerebral cortex, olfactory bulb and tubercle [6, 23, 33-35].
However, some discrepancies exist in the literature, mainly due to
different techniques to measure 5-HT6 mRNA and receptors. The
mRNA was observed in the cerebellum, hippocampus and
hypothalamus [23,33] in the pituitary and in the spinal cord [35],
but negative findings are also available [23]. Similarly, some
authors described it in the stomach [23], in dorsal root ganglia [35],
but others did not [23, 36]. The 5-HT6 mRNA was also found in the
immune system of rats [37] and in monkey blood mononuclear cells
[38, 39]. The presence of 5-HT6 receptors was reported in rat brain
regions, such as the striatum, nucleus accumbens, hippocampus and
olfactory tubercle [40-44, 29].
There are also some discrepancies between the localization of
the 5-HT6 receptor and its mRNA [33, 35, 41]. For example, intense
5-HT6 receptor immunoautoradiographic labelling was observed in
the cerebellum, where only weak to moderate levels of 5-HT6
receptors mRNA were found. Another mismatch is present in the
hippocampus, where a few 5-HT6 receptors were described with
high levels of 5-HT6-mRNA. Therefore, it seems that the 5-HT6
receptor in these regions is formed in somata and then moves to
dendrites or axons. The 5-HT6 receptors in the adult life are present
on GABAergic cells [34], but not on serotonergic [35], cholinergic
[45, 46] or dopaminergic neurons [41]. It can be concluded that 5-
HT6 receptors in adults are heteroreceptors and not autoreceptors.
In addition, 5-HT6 receptors appear in the developmental brain
where their stimulation favors embryonic interneurons migration
[47] and, according to Jackson et al. [48], they work as
autoreceptors.
In human tissues, mRNA for 5-HT6 receptors was
predominantly found in the caudate nucleus and nucleus
accumbens, with lower concentrations in the hippocampus and
amygdala, and very low levels in the thalamus, subthalamic nucleus
and substantia nigra [8, 29]. No 5-HT6-mRNA was detected in the
human spleen, stomach, small intestine, heart, liver, lung, skeletal
muscle, kidney, pancreas, placenta, testis, prostate and uterus [29].
5-HT6 RECEPTOR: AGONISTS AND ANTAGONISTS
The definition of agonist and antagonist is generally established
in vitro. Generally, the first step is the assessment of the affinity of
a compound for the receptor cloned on cell membranes or in native
tissues, and then its activity, if any, is tested with biological assays.
Monsma et al. (1993) and Ruat et al. (1993) [6, 23] were the
first to clone the rat receptor, whereas Kohen et al. (1996) [8] were
the first to clone the human 5-HT6 receptor, followed by others [7,
26]. Some discrepancies exist in compound affinities if the 5-HT6
receptor is radiolabelled with LSD or 5-HT. In fact, Boess et al.
(1997) [25] found that [3H]LSD and [3H]5-HT interact in a different
way with the 5-HT6 receptor, with the tryptamine derivatives
showing the highest affinity to [3H]5-HT binding sites, and the
ergoline derivatives the highest one to [3H]LSD binding sites. The
affinity values of compounds for rat and human 5-HT6 receptors
were quite similar, with the exclusion of metergoline (Ki = 400 nM
in Kohen et al., 1996 [8]; Ki = 30 nM in Monsma et al., 1993 [6]).
Nevertheless, radiolabelled LSD is preferred to 5-HT for screening
studies.
It is evident from the literature, that the 5-HT6 receptor in mice
is different from that of rats and humans. In fact, no specific 5-HT6
receptor binding was found in mouse brain [29, 30]; in addition to
the paucity of the 5-HT6 receptors, its mRNA is also very low [29].
However, Bibancos et al. (2007) could measure 5-HT6 receptor
mRNA expression in prefrontal cortex, hypothalamus, hippo-
campus and midbrain of mice [31]. Some binding signal was found,
however, by using mouse striatal neurons in culture [28], or cloning
the receptors in cells [29]. By using mouse 5-HT6 receptor cloned
in cells, however, its pharmacology does not resemble that of rats or
humans [29].
Regarding the biological activity of the compounds showing
affinity for the 5-HT6 receptors, it appears that the definition of
such an activity depends on the biological system used. At least
three different second-messenger systems have been described for
5-HT6 receptors: one linked to the third intracellular loop and G
protein [49, 25, 50-52], another linked to the terminal cytoplasmatic
part of the receptor protein through fyn-kynase activity [53, 54],
and the third associated with K+ channels [46]. Therefore, adenylate
cyclase (AC) measurements [25, 55, 50, 52, 56-59] and [35S]GTPS
binding [60, 56] are used to evaluate the interaction with the G
proteins, and fyn-kinase activity for the interaction with the
terminal part of the receptor protein [61].
Different results have been obtained when adenylate cyclase is
used in absence or presence of forskolin [52]. Moreover, some
antagonists (SB271046, Ro04-6790 and clozapine) on silent 5-HT6
receptors may behave as inverse agonists upon a constitutively
active mutant 5-HT6 receptor [24, 62, 52]. The agonist
WAY181187 may behave as a full agonist on adenylate cyclase
[63], or as a partial agonist on [35S]GTPS binding [57].
Mice, again, do not appear a suitable animal species to study
the function of 5-HT6 receptor ligands. LSD, for instance, in
contrast to its partial agonism observed in NCB-20 or HEK-293
cells cloned with the rat 5-HT6 receptor [20, 25], behaved as full
agonist in striatal neurons in culture [28].
Only a few compounds were described in depth regarding their
in-vitro pharmacology. The claimed 5-HT6 receptor antagonists, Ro
04-6790 and Ro63-0563 were reported to be competitive, but only
the former can cross the blood-brain barrier [64]. Subsequently, Ro
65-7199 was found to possess a better lypophilic profile than Ro
04-6790 [65]. Other 5-HT6 receptor antagonists are represented by
SB699929 [66, 67], SB357134 [50, 68] and SB399885 [69] which
appear to be pharmacokinetically and pharmacologically better than
SB271046 [70] and SB258585 [42]. Regarding other 5-HT6
receptor antagonists, the available information on PRX-07034 [71],
BVT74316 and SUVN594/504 [17], BVT5182 [72], Ro65-7199
and Ro66-0074 [73], is very scarce.
2-Ethyl-5-methoxy-N,n-dimethyltryptamine (EMDT) [74],
WAY466 [75], E-6801 [52], LY586713 [76], WAY208466 and
Serotonin Receptors of Type 6 (5-HT6) Current Medicinal Chemistry, 2011 Vol. 18, No. 1 3
WAY181187 [77, 63], R-13c [78] have been claimed to be 5-HT6
receptor agonists. Recently, a new 5-HT6 receptor agonist (ST1936)
has been presented at an international meeting [79]. Generally, the
5-HT6 receptor agonists are a few, and only WAY181187 has been
more widely used.
However, several papers have been published on the chemistry
of 5-HT6 receptor ligands and on their efficacy as agonists and
antagonists by using adenylate cyclase as index of activity [74, 80-
83, 78, 84-89, 57, 90-98, 58, 59, 99-104].
ANTAGONISM OF 5-HT6 RECEPTORS: A BEHAVIORAL
SYNDROME
According to some authors, the blockade of 5-HT6 receptor
function provokes a peculiar behavioral syndrome made up by
yawning, stretching and chewing. This was observed by using 5-HT
antisense oligonucleotides (AO) complementary to bases 1 to 18 of
the rat 5-HT6 cDNA: in this case the number of 5-HT6 receptors
was reduced by 30% in the frontal cortex [105]. However, such a
syndrome was not observed by others, who used the same
techniques [44, 41, 106].
As far as the use of 5-HT6 antagonists are concerned, Ro04-
6790 and other Roche antagonists [64, 107, 65] were reported to
elicit a yawning, stretching and chewing. The antagonist SB271046
was reported both to induce [108, 109] and not to induce [110] the
syndrome, while the antagonist SB357134 did not provoke any
syndrome [111]. Therefore, it is uncertain whether the 5-HT6
receptor blockade may induce any spontaneous behavioral effect
[112].
NEUROCHEMISTRY AND ELECTROPHYSIOLOGY OF 5-
HT6 RECEPTORS
Data in the field of neurochemistry and electrophysiology are
inconsistent. In brain slices, acetylcholine concentration was found
to be increased by two 5-HT6 receptor antagonists, both in vitro
[113] and in vivo [9], and decreased by the 5-HT6 receptor agonist,
WAY181187 in vivo [63]. At variance with these findings,
electrophysiological data showed that 5-HT depolarized striatal
cholinergic interneurons partially, via a direct stimulation of 5-HT6
receptors [46, 113]. In microdialysis studies, increased
acetylcholine levels were observed after the 5-HT6 receptor
antagonist SB399885 in the frontal cortex [114], but not after the
other antagonist Ro04-6790 in the hippocampus [115].
As far as the glutamate is concerned, 5-HT6 receptor
antagonists increased its extracellular concentration in the frontal
cortex both in vivo by SB271046 [116-118], and in vitro by
SB357134 [113]. The agonist WAY181187 decreased glutamate in
vitro but not in vivo [63].
Regarding striatal GABA, it was increased by the antagonist
SB357134 in vitro [113] and by the agonist WAY181187 in vivo
[63]. In vitro, electrophysiological investigations revealed that
WAY181187 increased spontaneous inhibitory postsynaptic
currents (sIPSC) frequency recorded from hippocampal CA1
neurons [119]: this is consistent with the reported presence of 5-
HT6 receptors on GABAergic neurons [45].
The role of 5-HT6 receptors in modulating catecholamines is
even more complex. The 5-HT6 antagonist SB271046 increased
catecholamine contents in the frontal cortex, when administered
orally [120], but not subcutaneously [116, 117]. In contrast to the
subcutaneous route, the oral administration allows the compound to
pass through the liver where it may be metabolized, but no
information is available on possible active metabolite(s). However,
another antagonist, SB258510, did not change the dopamine
content in the cortex [121], but SB271046 was reported to increase
dopamine release in the cochlea [122]. Furthermore, it should be
noted that also a recently developed 5-HT6 agonist (ST1936 [79])
was shown to increase catecholamine content in the cortex and that
such an effect was reversed by the antagonist SB271046, which was
inactive given “per se” [123].
Electrophysiological studies in vivo [124] showed that the
number of active dopaminergic cells was decreased in the ventral
tegmental area and unchanged in the substantia nigra, after a single
administration of the 5-HT6 antagonist SB270146, whereas, after
repeated SB271046 administration, it was increased in the
substantia nigra and unchanged in the ventral tegmental area.
THERAPEUTICAL POTENTIALS OF 5-HT6 RECEPTORS
In line with the difficulty to interpret the aforementioned
results, the potential therapeutic effects of modulating 5-HT6
receptors are still unclear.
Both 5-HT6 receptor antagonists [125-127, 69, 128, 129] and
agonists [130, 131] have been reported in animal models to possess
antidepressant potential; to be cognitive enhancers [4, 132-135,
108, 136- 141, 114, 142-152, 11, 53, 153, 75, 154, 155]; and to
exert anti-obesity effects [156-160]).
Antipsychotics were shown to bind to 5-HT6 receptors and
behaved as antagonists [6, 7, 161, 8, 60, 162]. However, the
usefulness of 5-HT6 receptor modulation for the treatment of
schizophrenia is premature [163-166, 124, 71, 167, 146, 168].
The 5-HT6 receptors have also been involved in analgesic
effects [169, 170], in the mode of action of drugs of abuse [121,
171-175], in sleep-wake regulation [176], and in seizures [177,
178]. However, they do not seem to be involved in animal models
of Parkinson’s disease [179].
The 5-HT6 gene polymorphism has been associated with suicide
[180], self-trascendence [181], executive cognition [182],
Parkinson’s disease [183], and treatment response to major
depressive disorder [184]. Contrasting results were found in the
polymorphism associated with Alzheimer’s disease [185-187], but a
decreased 5-HT6 receptor density was reported in the cortex of
patients suffering from this disorder [188]. No 5-HT6 gene
polymorphism was found in schizophrenia [189-192] or mood
disorders [190, 193].
CONCLUSIONS
The field of 5-HT6 receptors is still unclear and rapidly
evolving. Both 5-HT6 receptor agonists and antagonists seem to
share similar pharmacological properties. The available 5-HT6
receptor antagonists may poorly cross the blood-brain barrier, and
the number of 5-HT6 receptor agonists is scarce. Moreover, the
information about receptor selectivity and possible active
metabolite(s) is meager, and, similarly, experimental findings are
not always congruent [111, 194].
A characteristic of the 5-HT6 receptor is its rapid
desensitization. In fact, the cloned rat 5-HT6 receptor in HEK-293
cells undergoes fast desensitization, without receptor down-
regulation [195]. Therefore, some activities of 5-HT6 agonists may
depend on their agonistic properties within shorter times, but, due
to rapid receptor desensitization, an antagonistic action may appear
after longer periods. If so, the time course of the effects or time of
incubation may become crucial to understand some discrepancies.
Another consideration is that the definition of agonist and
antagonist derives from experiments with AC with the formation of
cyclic adenosine 3’,5’-monpophosphate (cAMP). The cAMP is
involved in the pharmacological cascade that leads to the activation
of a regulator of gene expression, the cAMP response element
(CRE) binding protein (CREB). cAMP can induce activation of
CREB by phosphorilating Ser133 via cAMP-dependent protein
4 Current Medicinal Chemistry, 2011 Vol. 18, No. 1 Marazziti et al.
kinase A (PKA). PKA may also interfere with the other 5-HT6
receptor-mediated biological activity: fyn-kinase activity, linked to
the carboxyl-terminal region of 5-HT6 receptors, and that can
activate extracellular signal-regulated kinase (ERK)1/2.
When the 5-HT6 receptor was co-expressed in HEK293 cells
with AC type 1 (AC1), type 5 (AC5) and type 8 (AC8), the receptor
stimulation only activated AC1 [55]. 5-HT6 receptors and AC1
have been shown to be mainly expressed in the hippocampus and
cerebellum, whereas 5-HT6 receptors and AC5 are mainly
expressed in the striatum and nucleus accumbens [55]. For this
reason, one cannot exclude that there exists a certain regionality of
5-HT6 receptor-mediated events. This might explain some odd
findings [76]: the 5-HT6 receptor agonist LY586713 increased Arc
nRNA in hippocampus and this effect was blocked by the 5-HT6
receptor antagonist SB271046, which was inactive “per se”;
however, both LY586713 and SB271046 increased Arc nRNA in
the cortex, in the same study.
As mentioned before, it should be noted that there is a third way
to exert biological activity after 5-HT6 receptor stimulation:
depolarization involving K+ channel opening [46]. A putative role
of 5-HT6 receptors in regulating Na+/K+-ATPase was also
suggested [196].
Finally, one has to consider that the expression of 5-HT6
receptors may depend on circulating adrenal corticoids, that is to
say, by the level of stress of the tested animals [109, 197, 198 ].
In conclusion, the role and the potential therapeutical use of 5-
HT6 Receptor ligands are not yet clearly understood, despite the
fact that some of them are in clinical development.
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