Svenningsson P, Tzavara ET, Liu F, Fienberg AA,
Nomikos GG, Greengard P.
DARPP-32 mediates serotonergic neurotransmission
in the forebrain.
Proc Natl Acad Sci U S A 2002 Mar 5;99(5):3188-93
"Here we report that serotonin regulates DARPP-32 phosphorylation both in
vitro and in vivo. Stimulation of 5-hydroxy-tryptamine (5-HT4 and 5-HT6) receptors
causes an increased phosphorylation state at Thr34DARPP-32, the protein
kinase A site, and a decreased phosphorylation state at Thr75DARPP-32, the
cyclin-dependent kinase 5 site. Furthermore, stimulation of 5-HT2 receptors increases
the phosphorylation state of Ser137DARPP-32, the casein kinase-1 site. Behavioral
and gene transcriptional effects induced by compounds that selectively release
serotonin were greatly reduced in DARPP-32 knockout mice." [Full
Boess, Frank G., Riemer, Claus, Bos, Michael,
Bentley, Jane, Bourson, Anne, Sleight, Andrew J.
Receptor-Selective radioligand [3H]Ro 63-0563 Labels 5-Hydroxytryptamine Receptor
Binding Sites in Rat and Porcine Striatum
1998 54: 577-583 [Full
Curr Opin Investig Drugs 2001 Jan;2(1):118-22
"Data recently presented at the Society for Neuroscience annual meeting in
November 2000 demonstrated that administration of SB-271046 resulted in a signficant
increase in glutamate and aspartate levels in the frontal cortex, without affecting
noradrenaline, dopamine or 5-HT levels. This was stated to suggest that 5-HT6
antagonists might therefore be useful for treating cognitive dysfunction ."
ML, Bentley JC, Sleight AJ, Marsden CA, Fone KC.
A role for 5-ht6
receptors in retention of spatial learning in the Morris water maze.
Neuropharmacology 2001 Aug;41(2):210-9
"This study investigates the effect
of intracerebroventricular administration of a 5-ht6 antisense oligonucleotide
(AO) complementary to bases 1-18 of the rat 5-ht6 cDNA initiation sequence (Mol.
Pharmacol. 43 (1993) 320) (1.5 microg twice daily for six days) and i.p. injection
of a selective 5-ht6 receptor antagonist Ro 04-6790 (10 or 30 mg/kg once daily
for three days) on acquisition and retention in the Morris water maze. Neither
the 5-ht6 AO (which reduced cortical [3H]-LSD binding sites by 10-16%) nor Ro
04-6790 affected acquisition, but both enhanced retention of the learned platform
position such that rats spent significantly longer searching the trained platform
position than any other area during the probe tests. Furthermore, neither AO nor
Ro 04-6790 had any effect on the time taken to reach a raised visible platform,
indicating that visual acuity was unimpaired. In addition, AO reduced both food
consumption and body weight and the later effect was also seen following Ro 04-6790,
suggesting a role for the 5-ht6 receptor in the regulation of feeding. Hence,
while the underlying mechanism remains unclear, enhanced retention of spatial
learning following both AO and 5-ht6 antagonist administration strongly indicate
a role for this receptor in memory processes." [Abstract]
Stefulj J, Jernej B, Cicin-Sain L, Rinner I, Schauenstein K.
mRNA expression of serotonin receptors in cells of the immune tissues of the
Brain Behav Immun 2000 Sep;14(3):219-24
13 rat 5-HT receptor genes cloned so far were examined in ex vivo isolated spleen,
thymus, and peripheral blood lymphocytes, as well as in mitogen-stimulated spleen
cells. Positive signals were obtained for 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT6,
and 5-HT7 receptor mRNAs in all three compartments. Mitogen (ConA and PWM) stimulated
cells additionally expressed mRNA corresponding to the 5HT-3 receptor subtype.
In contrast, 5-HT1A, 5-HT1D, 5-HT2C, 5-HT4, 5-HT5A, and 5-HT5B mRNAs were not
detected in any of the examined cell populations." [Abstract]
Branchek, Theresa A., Blackburn, Thomas P.
as Emerging Targets for Drug Discovery
Annu. Rev. Pharmacol.
Toxicol. 2000 40: 319-334
"Surprisingly, 5-ht6 receptors appear to regulate
cholinergic neurotransmission in the brain, rather than the expected interaction
as modulators of dopaminergic transmission. This interaction predicts a possible
role for 5-ht6 receptor antagonists in the treatment of learning and memory disorders."
Tsai SJ, Liu HC, Liu TY, Wang YC, Hong CJ.
analysis of the 5-HT6 receptor polymorphism C267T in Alzheimer's disease.
Neurosci Lett 1999 Dec 3;276(2):138-9
"Statistical analysis showed a
significant difference in the genotype and gene frequencies between the AD group
and the normal controls (P = 0.006; and P = 0.023, respectively). These findings
indicate that the 267C allele of the 5-HT6 gene is a risk factor for AD."
Hamon M, Doucet E, Lefevre K, Miquel MC, Lanfumey L, Insausti R, Frechilla
D, Del Rio J, Verge D.
Antibodies and antisense oligonucleotide
for probing the distribution and putative functions of central 5-HT6 receptors.
Neuropsychopharmacology 1999 Aug;21(2 Suppl):68S-76S
"Studies using polyclonal
anti-5-HT6 receptor antibodies and an antisense oligonucleotide were performed
in order to investigate further the function(s) of 5-HT6 receptors in the rat
brain. Immunocytochemistry at the light and electron microscope levels showed
that 5-HT6 receptors are mainly confined to the dendritic compartment, suggesting
that they could mediate 5-HT actions on neuronal firing. In some limbic areas,
5-HT6 receptor-like immunoreactivity is also associated with neuronal cilia with
yet unknown functions. Continuous i.c.v. infusion with an antisense oligonucleotide
for 3-4 days resulted in decreased 5-HT6 receptor-like immunostaining of the nucleus
accumbens and anxiogenic behaviours in the social interaction and elevated plus
maze tests." [Abstract]
Routledge, Carol, Bromidge, Steven M., Moss, Stephen
F., Price, Gary W., Hirst, Warren, Newman, Helen, Riley, Graham, Gager, Tracey,
Stean, Tania, Upton, Neil, Clarke, Stephen E., Brown, Anthony M., Middlemiss,
Characterization of SB-271046: A potent, selective and
orally active 5-HT6 receptor antagonist
Br. J. Pharmacol.
2000 130: 1606-1612
"SB-271046 produced an increase in seizure threshold
over a wide-dose range in the rat maximal electroshock seizure threshold (MEST)
test, with a minimum effective dose of 0.1 mg kg-1 p.o. and maximum effect at
4 h post-dose. The level of anticonvulsant activity achieved correlated well with
the blood concentrations of SB-271046 (EC50 of 0.16 µM) and brain concentrations
of 0.01 0.04 µM at Cmax.
together with the observed anticonvulsant activity of other selective 5-HT6 receptor
antagonists, SB-258510 (10 mg kg-1, 2 6 h pre-test) and Ro 04-6790 (1
30 mg kg-1, 1 h pre-test), in the rat MEST test, suggest that the anticonvulsant
properties of SB-271046 are likely to be mediated by 5-HT6 receptors." [Abstract]
Boess FG, Monsma FJ Jr, Sleight AJ.
of residues in transmembrane regions III and VI that contribute to the ligand
binding site of the serotonin 5-HT6 receptor.
"We have examined the ligand binding site of the
serotonin 5-HT6 receptor using site-directed mutagenesis. Replacing the highly
conserved Asp106 in transmembrane region III by asparagine eliminated D-[3H]-lysergic
acid diethylamide ([3H]LSD) binding to the mutant receptor transiently expressed
in HEK293 cells. The potency of 5-HT and LSD to stimulate adenylyl cyclase was
reduced by 3,600- and 500-fold, respectively, suggesting that an ionic interaction
between the positively charged amino group of 5-HT and D106 is essential for high-affinity
binding and important for receptor activation. In addition, basal cyclic AMP levels
in cells expressing this mutant were increased. Mutation of a tryptophan residue
one helix turn toward the extracellular side of transmembrane region III (Trp102)
to phenylalanine produced significant changes in the binding affinity and potency
of several ligands, consistent with a role of this residue in the formation of
the ligand binding site. The exchange of two neighboring residues in the carboxy-terminal
half of transmembrane region VI (Ala287 and Asn288) for leucine and serine resulted
in a mutant receptor with increased affinities (seven- to 30-fold) for sumatriptan
and several ergopeptine ligands. The identification of these interactions will
help to improve models of the 5-HT6 receptor ligand binding site." [Abstract]
Frank G., Monsma, Frederick J., Jr., Meyer, Valerie, Zwingelstein, Catherine,
Sleight, Andrew J.
Interaction of Tryptamine and Ergoline Compounds
with Threonine 196 in the Ligand Binding Site of the 5-Hydroxytryptamine6 Receptor
Mol Pharmacol 1997 52: 515-523
"The combination of site-directed mutagenesis
(guided by knowledge obtained for related receptors) with a series of related
ligands differing in a particular structural feature has allowed the identification
of a specific interaction between Thr196 in transmembrane region V of the 5-HT6
receptor and the indole nitrogen of N1-unsubstituted ergolines and tryptamines."
Sleight AJ, Monsma FJ Jr, Borroni E, Austin RH, Bourson A.
Effects of altered 5-ht6 expression in the rat: functional studies using
Behav Brain Res 1996;73(1-2):245-8
"Rats were treated with either saline, antisense (AO) or scrambled oligonucleotides
(SO) for 4 days. Treatment with AO reduced the number of [3H]LSD binding sites
in the frontal lobes by 30% but had no significant effect on the number of 5-HT1A
and 5-HT2A receptor binding sites in the cortex of the rats. A behavioural syndrome
of yawning, stretching and chewing, however, was observed in AO treated rats but
not in any of the other treatment groups. This AO-specific behaviour had returned
to normal 5 days after cessation of the oligodeoxynucleotide treatment."
R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR,
Roth BL, Hamblin MW.
Cloning, characterization, and chromosomal
localization of a human 5-HT6 serotonin receptor.
"The human 5-HT6 amino acid sequence is 89% similar
to the corrected rat sequence. The recombinant human 5-HT6 receptor is positively
coupled to adenylyl cyclase and has pharmacological properties similar to the
rat receptor with high affinity for several typical and atypical antipsychotics,
including clozapine. The receptor is expressed in several human brain regions,
most prominently in the caudate nucleus. The gene for the receptor maps to the
human chromosome region 1p35-p36. This localization overlaps that established
for the serotonin 5-HT1D alpha receptor, suggesting that these may be closely
Dawson LA, Nguyen HQ, Li P.
The 5-HT(6) receptor
antagonist SB-271046 selectively enhances excitatory neurotransmission in the
rat frontal cortex and hippocampus.
"Preclinical evidence has suggested a possible role
for the 5-HT(6) receptor in the treatment of cognitive dysfunction. However, currently
there is little neurochemical evidence suggesting the mechanism(s) which may be
involved. Using the selective 5-HT(6) antagonist SB-271046 and in vivo microdialysis,
we have evaluated the effects of this compound on the modulation of basal neurotransmitter
release within multiple brain regions of the freely moving rat. SB-271046 produced
no change in basal levels of dopamine (DA), norepinephrine (NE) or 5-HT in the
striatum, frontal cortex, dorsal hippocampus or nucleus accumbens. Similarly,
this compound had no effect on excitatory neurotransmission in the striatum or
nucleus accumbens. Conversely, SB-271046 produced 3- and 2-fold increases in extracellular
glutamate levels in both frontal cortex and dorsal hippocampus, respectively.
These effects were completely attenuated by infusion of tetrodotoxin but unaffected
by the muscarinic antagonist, atropine. Here we demonstrate for the first time
the selective enhancement of excitatory neurotransmission by SB-271046 in those
brain regions implicated in cognitive and memory function, and provide mechanistic
evidence in support of a possible therapeutic role for 5-HT(6) receptor antagonists
in the treatment of cognitive and memory dysfunction." [Abstract]
C, Martres MP, Lefevre K, Miquel MC, Verge D, Lanfumey L, Doucet E, Hamon M, el
Immuno-localization of serotonin 5-HT6 receptor-like
material in the rat central nervous system.
Brain Res 1997
"Immunoautoradiographic experiments with antibodies
affinity-purified on Affi-Gel coupled to the peptide antigen showed that 5-HT6-like
immunoreactive material was abundant in the olfactory tubercle (plexiform layer),
cerebral cortex (frontal and entorhinal areas), nucleus accumbens, striatum, hippocampus
(strata oriens and radiatum of the CA1 area, molecular layer of the dentate gyrus)
and the molecular layer of the cerebellum. A specific immunolabeling, but at moderate
intensity, was also observed in the thalamus, substantia nigra, superficial layer
of the superior colliculus, motor trigeminal nucleus and facial nucleus. In contrast,
no 5-HT6-like immunoreactive material was found in white matter areas. As the
regional distribution of 5-HT6 receptor-like immunoreactivity matched generally
that previously found for the 5-HT6 receptor mRNA, one could infer that this receptor
protein is addressed in the vicinity of its synthesis site, i.e. on somas and/or
dendrites. Indeed, immunohistochemistry at the light and electron microscope level
showed that 5-HT6-like immunoreactivity was associated with dendritic processes
in both the striatum and the dentate gyrus of the hippocampus. The relative abundance
of 5-HT6 receptor-like immunoreactivity in extrapyramidal and limbic areas suggests
that 5-HT6 receptors may participate in the serotoninergic control of motor function
and mood-dependent behavior, respectively." [Abstract]
Lauren P. Baker, Mark D. Nielsen, Soren Impey, Mark
A. Metcalf, Steven W. Poser, Guy Chan, Karl Obrietan, Mark W. Hamblin, and Daniel
Stimulation of Type 1 and Type 8 Ca2+/Calmodulin-sensitive
Adenylyl Cyclases by the Gs-coupled 5-Hydroxytryptamine Subtype 5-HT7A Receptor
J. Biol. Chem. 273: 17469-17476, July 1998.
summary, these data demonstrate that 5-HT6 acts as a typical Gs-coupled receptor
by stimulating AC5, but not AC1 or AC8. The discovery that 5-HT7A stimulates AC1
and AC8 through increases in intracellular Ca2+ provides a novel mechanism for
serotonergic regulation of intracellular cAMP in the brain and other tissues."
East SZ, Burnet PW, Leslie RA, Roberts JC, Harrison PJ.
receptor binding sites in schizophrenia and following antipsychotic drug administration:
Autoradiographic studies with [125I]SB-258585.
"In summary, [(125)I]SB-258585 is a suitable radioligand
for studies of human brain 5-HT(6)R binding sites and shows that their distribution
is broadly similar to that of the rodent. The lack of effect of schizophrenia
or antipsychotic drug administration on [(125)I]SB-258585 binding suggests that
an altered receptor density does not contribute to any involvement which the 5-HT(6)R
may have in the disease or its treatment." [Abstract]
Masellis M, Basile VS, Meltzer HY, Lieberman JA, Sevy S, Goldman DA, Hamblin
MW, Macciardi FM, Kennedy JL.
Lack of association between the T-->C
267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response
to clozapine in schizophrenia.
Schizophr Res 2001 Jan 15;47(1):49-58
O, Shinkai T, Hori H, Nakamura J.
Novel polymorphism in the 5'-upstream
region of the human 5-HT6 receptor gene and schizophrenia.
Neurosci Lett 2001 Sep 7;310(1):17-20
"Our results suggest that the 5-HT6
receptor gene polymorphism does not confer increased susceptibility to schizophrenia."
T, Ohmori O, Kojima H, Terao T, Suzuki T, Abe K.
of the 5-HT6 receptor gene in schizophrenia.
Am J Med Genet
1999 Apr 16;88(2):120-2
"No significant positive association between
the 5-HT6 receptor genotype and schizophrenia was observed. Our results suggests
that the 267C/T polymorphism of the 5-HT6 receptor gene may not be involved in
the susceptibility to schizophrenia." [Abstract]
DC, Hagan JJ.
5-HT6 receptor antagonists enhance retention of a
water maze task in the rat.
Psychopharmacology (Berl) 2001
" In the water maze, administration of SB-271046-A or
SB-357134-A (3 or 10 mg/kg) had no effect on learning per se. At 10 mg/kg, however,
both compounds produced a significant improvement in retention of a previously
learned platform position when tested 7 days after training. By contrast, the
acetylcholinesterase inhibitor, Aricept (donepezil, 0.1, 0.3 mg/kg PO) had no
effect in this task."
R, Fashingbauer LA, Heidmann DE, Guthrie CR, Hamblin MW.
of the mouse 5-HT6 serotonin receptor and mutagenesis studies of the third cytoplasmic
Brain Res Mol Brain Res 2001 Jun 20;90(2):110-7
"These data suggest that constitutive activity may be important to 5-HT6
receptor activity in vivo and that, unlike some other G-protein coupled receptors,
alteration in the BBXXB CIII-loop motif reduces rather than further activates
basal activity of the murine 5-HT6 receptor." [Abstract]
M, Yoshioka M.
[Possible involvement of serotonin receptors in anxiety
Nippon Yakurigaku Zasshi 2000 Jan;115(1):39-44
"Inactivation of mRNA encoding 5-HT6 receptors using antisense oligonucleotide
produced decreases in cortical 5-HT release enhanced by anxiety. These observations
lead to the suggestion that different mechanisms, mediated by various 5-HT receptors,
are involved in the pathogenesis of anxiety." [Abstract]
DJ, Meador-Woodruff JH.
Ionotropic glutamate receptor modulation
of 5-HT6 and 5-HT7 mRNA expression in rat brain.
"MK-801 treatment induced a dose-dependent decrease
in striatal 5-HT6 receptor mRNA levels; similarly, both aniracetam and NBQX treatments
also led to decreases in striatal 5-HT6 receptor mRNA levels. Hippocampal 5-HT6
and 5-HT7 receptor expression were not dramatically affected by any of the treatments.
To our knowledge, this is the first demonstration of the regulation of striatal
5-HT6 receptor mRNA expression, and provides neurochemical anatomical evidence
for the interaction of serotonergic and glutamatergic systems."
Pena-Rangel MT, Mercado R, Hernandez-Rodriguez J.
Regulation of glial Na+/K+-ATPase by serotonin: identification of participating
Neurochem Res 1999 May;24(5):643-9
these results show that serotonin modulates glial Na+/K+-ATPase activity in the
brain, apparently not through only one type of 5-HT receptor. It seems that the
receptor system involved is different according to the brain region. In cerebral
cortex, the response seems to be mediated by 5-HT1A as well as in hippocampus
but not in cerebellum where 5-HT6 appears as the receptor system involved."
Jane C., Bourson, Anne, Boess, Frank G., Fone, Kevin C.F., Marsden, Charles A.,
Petit, Nadine, Sleight, Andrew J.
Investigation of stretching behaviour
induced by the selective 5-HT6 receptor antagonist, Ro 04-6790, in rats
Br. J. Pharmacol. 1999 126: 1537-1542
"These data suggest that systemic
injection of the 5-HT6 antagonist, Ro 04-6790, produces a stretching behaviour
that appears to be mediated by an increase in cholinergic neurotransmission in
the CNS and which could be a useful functional correlate for 5-HT6 receptor blockade.
There is no evidence for dopamine D2-like receptor involvement in this behaviour."
A, Boess, FG, Bos, M, Sleight, AJ
Involvement of 5-HT6 receptors
in nigro-striatal function in rodents
Br. J. Pharmacol.
1998 125: 1562-1566
"Ro 04-6790 (3, 10 and 30 mg kg(-1) i.p.) did not
itself induce rotational behaviour in rats with unilateral 6- hydroxydopamine
(6-OHDA) lesions of the medial forebrain bundle nor did it affect the rotational
behaviour induced by either L-Dopa or amphetamine. 5-HT6 receptor antagonism inhibited
the rotational behaviour of 6-OHDA lesioned rats induced by treatment with the
muscarinic antagonists scopolamine and atropine. The data support earlier conclusions
from experiments with antisense oligonucleotides that the 5-HT6 receptor is involved
in the control of acetylcholine neurotransmission in the rat brain." [Abstract]
Hirst, Warren D., Minton, Jayne A.L., Bromidge, Steven M.,
Moss, Stephen F., Latter, Alison J., Riley, Graham, Routledge, Carol, Middlemiss,
Derek N., Price, Gary W.
Characterization of [125I]-SB-258585 binding
to human recombinant and native 5-HT6 receptors in rat, pig and human brain tissue
Br. J. Pharmacol. 2000 130: 1597-1605
"The pKi rank order of potency
for a number of compounds, determined in competition binding assays with [125I]-SB-258585,
at human caudate putamen membranes was: SB-271046>SB-258585>SB-214111>methiothepin>clozapine>5-Me-OT>5-HT>Ro
profiles were obtained from pig and rat striatal membranes and recombinant 5-HT6
receptors; data from the latter correlated well with [3H]-LSD binding." [Abstract]
A, Herrick-Davis K, Teitler M.
Creation, expression, and characterization
of a constitutively active mutant of the human serotonin 5-HT6 receptor.
"The serotonin 5-HT(6) receptor, a G-protein-coupled
receptor, displays high affinity for antipsychotic, antidepressant, and psychotropic
drugs. We created a constitutively active form of the human 5-HT(6) receptor in
order to probe the molecular domains of receptor activation and to determine if
inverse agonist activities of antipsychotic drugs contribute to their clinical
profile. Previous studies from our laboratory support a critical role for the
c-terminal region of the third intracellular loop (il3) in the activation of G(q)-coupled
serotonin receptors. In the present study, PCR-based mutagenesis was used to mutate
serine 267 (S6.34) in the c-terminal region of il3 to lysine (S267K). The native
and S267K 5-HT(6) receptors were expressed in COS-7 cells to study the functional
effects of the mutation. The S267K receptor shows 10-fold higher affinity for
serotonin than the native receptor and demonstrates agonist-independent activity.
Clozapine decreased the basal activity of the S267K receptor to vector control
levels. Therefore, we can conclude that the S267K mutation renders the 5-HT(6)
receptor constitutively active and that clozapine is an inverse agonist at the
mutant 5-HT(6) receptor. These results indicate that the c-terminal region of
il3 of the G(s)-coupled 5-HT(6) receptor is a key domain for G-protein coupling,
similar to the G(q)-coupled 5-HT receptors. The inverse agonist action of clozapine
indicates that drugs displaying competitive antagonist activity at native 5-HT(6)
receptors may display inverse agonist activity at the constitutively activated
form of the receptor." [Abstract]
Olsen MA, Nawoschik SP, Schurman BR, Schmitt HL, Burno M,
Smith DL, Schechter LE.
Identification of a human 5-HT6 receptor
variant produced by alternative splicing.
Brain Res Mol
Brain Res 1999 Feb 5;64(2):255-63
"The splicing pattern seen for this
transcript was not detected in rat or mouse whole brain cDNA by PCR due to the
lack of a consensus 5' donor site. Coexpression of the variant 5-HT6 transcript
and the full length 5-HT6 transcript was observed in caudate and substantia nigra
but not in hippocampus, cortex, cerebellum and thalamus. Transient transfection
of a 5-HT6 variant construct into Cos-7 cells demonstrated that a truncated receptor
was translocated to the membrane but appeared nonfunctional." [Abstract]
JL, Noble J, Widdowson J, Seckl JR.
Impact of adrenalectomy on 5-HT6
and 5-HT7 receptor gene expression in the rat hippocampus.
Brain Res Mol Brain Res 1997 Apr;45(1):182-6
"Here, we show that pharmacological
adrenalectomy increases 5-HT6 and 5-HT7 receptor mRNA expression in specific hippocampal
subfields, effects partly reversed by corticosterone replacement." [Abstract]