Affinage

HTR6

5-hydroxytryptamine receptor 6 · UniProt P50406

Length
440 aa
Mass
47.0 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTR6 (5-HT6R) is a serotonin-activated, Gs-coupled GPCR that positively couples to adenylyl cyclase to drive cAMP production, a property established for the rat, human, and pig receptors in heterologous cells and native brain tissue (PMID:8389146, PMID:7696602, PMID:8522988). The receptor displays robust constitutive (agonist-independent) activity that depends on the BBXXB motif and C-terminal residues of the third cytoplasmic loop, where mutations such as S267K lock the receptor in an active state and reveal that clinically used antagonists like clozapine behave as inverse agonists (PMID:11406289, PMID:12494404, PMID:16865095). Antagonist binding is governed by a defined pocket including residues W6.48, F6.52, and N6.55 (PMID:20078106). Constitutive Gs/cAMP signaling is amplified by physical interaction with neurofibromin through its PH domain, loss of which—via NF1 patient mutations or silencing—lowers basal cAMP and CREB phosphorylation in prefrontal cortex (PMID:27791021). The receptor nucleates distinct effector pathways through direct protein partners: its C-terminus binds the SH3 domain of Fyn kinase to activate ERK1/2 (PMID:17189269), and it constitutively associates with Cdk5, which phosphorylates Ser350 to drive agonist-independent, Cdc42-dependent neurite outgrowth (PMID:24880860). Downstream, agonist activation phosphorylates Thr34-DARPP-32 and Ser845-GluR1 independently of D1 receptors (PMID:17428998) and engages mTORC1 signaling implicated in memory and seizure regulation (PMID:30883547, PMID:25034463). HTR6 localizes to dendrites and neuronal primary cilia, where it controls cilia length and axon initial segment morphology (PMID:9037500, PMID:10432491, PMID:28931427). Functionally, the receptor modulates circuit activity by inhibiting corticostriatal glutamatergic transmission through pre- and postsynaptic mechanisms (PMID:21619890) and by elevating cortical GABAergic tone via local interneurons (PMID:17625499), collectively underpinning roles in instrumental learning, reward processing, and cholinergic neurotransmission (PMID:17192775, PMID:17631868, PMID:9884085).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1993 High

    Established the fundamental signaling identity of the receptor by showing it positively drives cAMP, defining it as a Gs-coupled GPCR.

    Evidence Transient transfection of COS-7 cells with cAMP accumulation assay (rat receptor)

    PMID:8389146

    Open questions at the time
    • Heterologous system only; native neuronal coupling not yet shown
    • No downstream effectors identified
  2. 1996 High

    Extended Gs/adenylyl cyclase coupling to the human receptor and revealed high affinity for typical and atypical antipsychotics, anchoring the receptor's pharmacological and clinical relevance.

    Evidence Recombinant human receptor expression, cAMP assay, radioligand binding, genomic cloning; corroborated in native striatal neurons and pig caudate membranes

    PMID:7696602 PMID:7845473 PMID:8522988

    Open questions at the time
    • Mechanism of antipsychotic action at the receptor not resolved
    • No structural basis for ligand binding
  3. 1997 Medium

    Determined where the receptor acts in neurons by localizing it to dendritic processes, indicating postsynaptic/dendritic signaling rather than axonal.

    Evidence EM immunohistochemistry in rat striatum and dentate gyrus; agonist potency rank order established in stable HEK293 cells

    PMID:9037500 PMID:9225298

    Open questions at the time
    • Trafficking determinants unknown
    • Cell-type specificity within regions not defined
  4. 1999 Medium

    Linked the receptor to tonic serotonergic control of behavior and identified a ciliary localization, while implicating it in cholinergic neurotransmission.

    Evidence icv antisense knockdown with radioligand binding and behavioral assays; EM immunocytochemistry to cilia; pharmacological antagonism in 6-OHDA lesion model

    PMID:10432491 PMID:8788511 PMID:9884085

    Open questions at the time
    • Molecular basis of ciliary targeting unknown
    • Indirect cholinergic effects vs direct receptor action not separated
  5. 2003 High

    Mapped the structural determinants of constitutive activity to the third cytoplasmic loop and demonstrated inverse agonism, reframing antagonists as agents that suppress agonist-independent signaling.

    Evidence Site-directed mutagenesis (BBXXB motif, S267K constitutively active mutant) with cAMP reporter assays in COS-7/JEG-3 cells

    PMID:11406289 PMID:12494404 PMID:16865095

    Open questions at the time
    • No full-length structure to explain constitutive activation
    • Physiological role of constitutive activity not yet established
  6. 2006 High

    Identified the first direct intracellular partner, showing the C-terminus binds Fyn via its SH3 domain to activate ERK1/2, revealing signaling beyond cAMP.

    Evidence Yeast two-hybrid, GST pulldown, reciprocal co-IP in two cell lines and rat brain, ERK1/2 phosphorylation assay

    PMID:17189269

    Open questions at the time
    • Functional consequence of ERK activation in vivo unresolved
    • Relationship between Fyn/ERK and cAMP pathways not integrated
  7. 2006 Medium

    Demonstrated a behavioral role by showing striatal overexpression selectively impairs instrumental (striatum-dependent) learning, reversible by antagonist.

    Evidence Viral overexpression in rat dorsomedial striatum, instrumental and Morris water maze tasks, pharmacological rescue with SB-258585

    PMID:17192775

    Open questions at the time
    • Circuit and molecular mediators of learning deficit not defined
    • Overexpression may not reflect endogenous levels
  8. 2007 Medium

    Connected the receptor to striatal/cortical signaling cascades and neurotransmitter circuits — phosphorylating DARPP-32 and GluR1, elevating cortical GABA, and modulating reward.

    Evidence Western blot phospho-protein analysis, in vivo microdialysis with antagonist and bicuculline blockade, viral overexpression in NAc with conditioned place preference

    PMID:17428998 PMID:17625499 PMID:17631868

    Open questions at the time
    • Cell-type origin of GABA elevation only inferred
    • Link between phosphorylation events and behavior not directly tested
  9. 2011 High

    Resolved the synaptic-level action of the receptor, showing it inhibits glutamatergic transmission via distinct pre- and postsynaptic mechanisms in striatum and cortex.

    Evidence Whole-cell patch-clamp in striatal and cortical slices with paired-pulse and miniature EPSC analysis, SB258585 blockade

    PMID:21619890

    Open questions at the time
    • Intracellular signaling underlying synaptic suppression not identified
    • In vivo relevance of slice findings not confirmed
  10. 2014 High

    Defined a constitutive, cAMP-independent signaling axis: Cdk5 binds and phosphorylates Ser350 to drive agonist-independent neurite growth via Cdc42, establishing the receptor as a regulator of neuronal morphogenesis.

    Evidence Proteomics, co-IP, in vitro kinase assay, S350A mutagenesis, siRNA, neurite assays in NG108-15 and primary neurons; parallel seizure/mTOR work in pilocarpine model

    PMID:24880860 PMID:25034463

    Open questions at the time
    • How Ser350 phosphorylation engages Cdc42 mechanistically unclear
    • Interplay between constitutive morphogenic signaling and Gs/cAMP not integrated
  11. 2016 High

    Identified neurofibromin as a partner that sustains constitutive Gs signaling, linking the receptor's basal activity to NF1 biology and prefrontal CREB signaling.

    Evidence Co-IP, siRNA, PH domain rescue, NF1 patient mutations, Nf1+/- mouse, cAMP and CREB phosphorylation assays

    PMID:27791021

    Open questions at the time
    • Structural basis of PH-domain/receptor interaction unknown
    • Clinical translation to NF1 cognitive phenotypes not established
  12. 2019 Medium

    Placed the receptor within a nutrient-sensing program, showing HTR6-mediated mTORC1 signaling is required for dietary-restriction-induced memory enhancement and hippocampal plasticity, complementing its control of cilia/AIS morphology.

    Evidence HTR6 loss-of-function in Drosophila and mouse, dendritic/spine morphology, LTP, mTORC1 assays; primary neuron cilia manipulation and APP/PS1 AD model

    PMID:28931427 PMID:30883547

    Open questions at the time
    • Direct biochemical link between receptor and mTORC1 not fully defined
    • Whether cilia and mTORC1 phenotypes share a common effector unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the receptor's multiple, partly parallel outputs — constitutive Gs/cAMP, Cdk5/Ser350-Cdc42 morphogenesis, Fyn/ERK, and mTORC1 — are integrated and selected within a single neuron remains unresolved.
  • No experimentally determined full-length receptor structure in the corpus
  • Effector pathway crosstalk and bias not dissected
  • Human disease causality beyond NF1-associated signaling not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 1
Localization
GO:0005929 cilium 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-112316 Neuronal System 2
Partners
CDK5FYNNF1

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 The rat 5-HT6 receptor, when transiently expressed in transfected COS-7 cells, is positively coupled to cyclic AMP (cAMP) production, establishing it as a Gs-coupled GPCR. Transient transfection of COS-7 cells followed by cAMP accumulation assay Biochemical and biophysical research communications High 8389146
1994 5-HT6 receptors are positively coupled to adenylyl cyclase in striatal neurons in culture, confirming native receptor coupling to cAMP in brain neurons. Primary striatal neuron culture with cAMP level measurement and radioligand binding ([125I]-LSD) Neuroreport High 7696602
1994 5-HT6 receptors in pig caudate membranes stimulate adenylyl cyclase activity; methiothepin and clozapine act as surmountable antagonists, establishing the native tissue pharmacological coupling profile. Adenylyl cyclase assay in pig brain caudate membranes with pharmacological characterization Naunyn-Schmiedeberg's archives of pharmacology Medium 7845473
1996 The human 5-HT6 receptor is positively coupled to adenylyl cyclase and has high affinity for typical and atypical antipsychotics including clozapine; the gene contains two introns in the third cytoplasmic loop and third extracellular loop. Recombinant expression, cAMP accumulation assay, radioligand binding, genomic cloning Journal of neurochemistry High 8522988
1997 5-HT6 receptor-like immunoreactivity is localized to dendritic processes in the striatum and dentate gyrus of the hippocampus, indicating the receptor is trafficked to dendrites rather than axons. Immunohistochemistry (light and electron microscopy) using polyclonal anti-5-HT6 receptor antibodies in rat brain Brain research Medium 9037500
1997 Stably expressed rat 5-HT6 receptor in HEK293 cells stimulates cAMP accumulation; rank order of agonist potency established; several compounds (LSD, lisuride, 2-methyl-5-HT, tryptamine, 5-benzyloxytryptamine) act as partial agonists relative to 5-HT. Stable transfection of HEK293 cells, radioligand binding ([3H]-LSD, [3H]-5-HT), cAMP accumulation assay Neuropharmacology High 9225298
1998 5-HT6 receptor is expressed in rat brain from embryonic day 12 onward and is positively coupled to adenylyl cyclase in stably transfected CHO cells; antipsychotic and antidepressant drugs block 5-HT-stimulated cAMP production. Stable transfection of CHO cells, [3H]-5-HT binding, adenylyl cyclase assay, RT-PCR for developmental expression Naunyn-Schmiedeberg's archives of pharmacology Medium 9606024
1998 Antisense oligonucleotide knockdown of 5-HT6 receptors in rat brain implicates the receptor in control of acetylcholine neurotransmission; 5-HT6 receptor antagonism (Ro 04-6790) in 6-OHDA lesioned rats inhibits scopolamine- and atropine-induced rotational behavior, supporting cholinergic modulation. Antisense oligonucleotide (icv infusion), pharmacological antagonism with Ro 04-6790, behavioral assessment in 6-OHDA lesion model British journal of pharmacology Medium 9884085
1999 5-HT6 receptor-like immunoreactivity is associated with neuronal cilia in some limbic brain areas; antisense knockdown reduces 5-HT6 immunostaining in nucleus accumbens and produces anxiogenic behavior. Immunocytochemistry (light and electron microscopy), icv antisense oligonucleotide infusion, behavioral tests (social interaction, elevated plus maze) Neuropsychopharmacology Medium 10432491
1999 Antisense oligonucleotide knockdown of 5-ht6 reduced cortical [3H]-LSD binding sites and caused a behavioral syndrome of yawning, stretching, and chewing, indicating the receptor is under tonic control of endogenous 5-HT. Phosphorothioate antisense oligonucleotide treatment (icv), radioligand binding ([3H]-LSD), behavioral observation Behavioural brain research Medium 8788511
2001 The mouse 5-HT6 receptor exhibits constitutive activity when transiently expressed in JEG-3 or COS-7 cells; point mutations in the BBXXB motif of the third cytoplasmic loop (K264I, K267A, A268R) reduce constitutive activity. Site-directed mutagenesis of the third cytoplasmic loop, cAMP-responsive reporter gene assay in JEG-3/COS-7 cells Brain research. Molecular brain research High 11406289
2003 Mutation of Ser267 to Lys in the C-terminal region of the third intracellular loop (S267K) renders the human 5-HT6 receptor constitutively active; clozapine acts as an inverse agonist at this constitutively active mutant, reducing basal cAMP to vector control levels. PCR-based site-directed mutagenesis, expression in COS-7 cells, cAMP accumulation assay Synapse (New York, N.Y.) High 12494404
2005 A 3D pharmacophore model for 5-HT6R antagonists identifies key binding residues: Asp3.32 for ionic interaction with the protonated amine, Ser5.43 and Asn6.55 for hydrogen bonding, and a hydrophobic pocket between TM3/4/5 and Phe6.52. Computational pharmacophore modeling (Catalyst) using 45 structurally diverse antagonists with experimental binding validation Journal of medicinal chemistry Low 15974573
2006 The C-terminal region of the 5-HT6 receptor interacts with the Fyn tyrosine kinase through Fyn's SH3 domain; activation of the 5-HT6 receptor activates ERK1/2 via a Fyn-dependent pathway. Yeast two-hybrid, GST pulldown assay, co-immunoprecipitation in two cell lines and rat brain, immunocytochemistry/immunohistochemistry, ERK1/2 phosphorylation assay The Journal of biological chemistry High 17189269
2006 Increased viral-vector-mediated overexpression of 5-HT6 receptors in rat dorsomedial striatum impairs acquisition of instrumental (striatum-dependent) learning but not Morris water maze (hippocampus-dependent) learning; this deficit is reversed by 5-HT6 antagonist SB-258585. Viral-mediated gene transfer to rat striatum (dorsomedial vs. dorsocentral), instrumental learning task, Morris water maze, pharmacological rescue with SB-258585 Neuropsychopharmacology Medium 17192775
2006 E-6801 and E-6837 are partial agonists at the rat 5-HT6 receptor; Ro 04-6790 and SB-271046 act as inverse agonists/antagonists; a constitutively active S267K mutant receptor confirms inverse agonist properties of antagonists. Site-directed mutagenesis (S267K constitutively active mutant), cAMP assay with and without forskolin co-stimulation, pharmacological characterization in COS-7 cells British journal of pharmacology High 16865095
2007 Selective 5-HT6 receptor agonists WAY-181187 and WAY-208466 increase extracellular GABA in rat frontal cortex, dorsal hippocampus, striatum, and amygdala; the GABA elevation in the frontal cortex is blocked by 5-HT6 antagonist SB-271046 and by intracortical bicuculline, implicating 5-HT6 in the activation of local GABAergic interneurons. In vivo microdialysis in rat brain, pharmacological blockade with SB-271046 and bicuculline, in vitro hippocampal slice glutamate measurement Neuropsychopharmacology High 17625499
2007 5-HT6 receptor agonism (EMDT) increases phosphorylation of Thr34-DARPP-32 and Ser845-GluR1 in brain slices and intact brain; these effects are independent of D1 receptor stimulation and can be blocked by the 5-HT6 antagonist SB271046. Western blot for phospho-protein levels in brain slices and in vivo, pharmacological blockade with SB271046, D1 receptor independence confirmed The Journal of neuroscience Medium 17428998
2008 5-HT6 receptor antagonists SB-271046 and SB-399885 increase NCAM polysialylation (PSA) of dentate granule cells in the hippocampus and entorhinal/perirhinal cortex in a dose-dependent manner, without increasing neurogenesis; they also enhance learning-associated polysialylation. Quantitative immunohistochemistry for NCAM PSA, BrdU incorporation for neurogenesis, chronic drug administration in rats Neuropharmacology Medium 18455201
2010 Site-directed mutagenesis identifies residues W6.48, F6.52, and N6.55 as critical for 5-HT6R antagonist binding; substitution of any of these with Ala fully abolishes the ability of compound 4 to block 5-HT-induced receptor activation. Site-directed mutagenesis, cAMP functional assay, homology modeling based on beta2-adrenoceptor structure Journal of medicinal chemistry High 20078106
2011 5-HT6 receptor activation by agonist ST1936 reduces the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in striatal medium spiny neurons (postsynaptic mechanism) and reduces only the frequency in cortical layer V pyramidal neurons (presynaptic or indirect mechanism); effects blocked by SB258585. Whole-cell patch-clamp electrophysiology in striatal and cortical brain slices, pharmacological blockade with SB258585, paired-pulse analysis, miniature EPSC recordings Neuropharmacology High 21619890
2014 5-HT6 receptor constitutively interacts with cyclin-dependent kinase 5 (Cdk5); Cdk5 phosphorylates the receptor at Ser350, and this phosphorylation is required for 5-HT6R-elicited neurite growth in NG108-15 cells and primary neurons. Neurite growth is agonist-independent (constitutive), requires Cdc42 activity, and is prevented by 5-HT6 inverse agonist SB258585. Mutation of Ser350 to Ala abolishes the effect. Proteomic strategy to identify interactors, co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (S350A), siRNA knockdown, neurite growth assay in NG108-15 cells and primary neurons Nature chemical biology High 24880860
2016 Neurofibromin (NF1 gene product) physically interacts with the 5-HT6 receptor and promotes its constitutive Gs/adenylyl cyclase signaling; disruption of the 5-HT6R–neurofibromin interaction via neurofibromin's Pleckstrin Homology (PH) domain, NF1 patient mutations, or neurofibromin silencing reduces constitutive cAMP signaling and CREB phosphorylation in prefrontal cortex. Co-immunoprecipitation, siRNA knockdown, PH domain expression/rescue, Nf1+/- mouse model, cAMP assay, CREB phosphorylation by western blot, in vivo 5-HT6 inverse agonist administration Proceedings of the National Academy of Sciences of the United States of America High 27791021
2016 5-HT6 receptor antagonist SB271046 (idalopirdine class) potentiates donepezil-induced increases in hippocampal theta and gamma oscillations and extracellular acetylcholine levels in rats; idalopirdine alone has no effect on these parameters. In vivo electrophysiology (brainstem stimulation-evoked hippocampal oscillations in anesthetized rats), in vivo microdialysis (freely moving rats), pharmacokinetic interaction assessment Neuropharmacology Medium 27039041
2017 5-HT6 receptor regulates the length and morphology of primary cilia in hippocampal neurons; overexpression elongates cilia, alters axon initial segment (AIS) morphology and AnkG/ARL13B localization, and reduces axonal length. Knockdown has opposite effects. These changes are linked to cognitive impairment in APP/PS1 AD model mice. Immunostaining, overexpression and siRNA knockdown in primary hippocampal neurons, APP/PS1 mouse model, behavioral testing (Morris water maze, Y-maze, fear conditioning) Alzheimer's research & therapy Medium 28931427
2019 HTR6 (5-HT6 receptor)-mediated mTORC1 signaling is required for dietary restriction-induced memory enhancement; HTR6 inactivation diminishes DR-induced hippocampal neurological alterations (reduced dendritic complexity, increased spine density, enhanced LTP), linking the receptor to a nutrient-sensing pathway. HTR6 knockout/inactivation in Drosophila and mouse, dendritic morphology analysis, spine density measurement, LTP recording, mTORC1 signaling assay PLoS biology Medium 30883547
2014 5-HT6 receptor blockade suppresses epileptic seizures and reduces mTOR activity in the pilocarpine rat model; HTR6 expression is upregulated in epileptic tissue, and SB-399885 (5-HT6 antagonist) suppresses both seizures and mTOR signaling, suggesting an HTR6/mTOR pathway in seizure regulation. Western blotting (HTR6 expression and mTOR activity), EEG recording, whole-cell patch clamp, pilocarpine rat model, pharmacological antagonism with SB-399885 ± rapamycin Molecular neurobiology Medium 25034463
2007 Increased 5-HT6 receptor expression in rat nucleus accumbens (via viral-mediated gene transfer) blocks cocaine conditioned place preference (CPP) but has no effect on acute locomotor response to cocaine or development of cocaine-induced locomotor sensitization; pharmacological antagonism of 5-HT6R facilitates CPP acquisition. Viral-mediated gene transfer to NAc, conditioned place preference, locomotor sensitization, pharmacological antagonism with Ro4368554 Biological psychiatry Medium 17631868

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation. Biochemical and biophysical research communications 333 8389146
1996 Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor. Journal of neurochemistry 305 8522988
1997 Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system. Brain research 256 9037500
2008 A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory. Trends in pharmacological sciences 236 19086256
2004 5-ht6 receptors. Current drug targets. CNS and neurological disorders 220 14965245
2008 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 203 18625457
2005 5-HT6 receptors: a novel target for cognitive enhancement. Pharmacology & therapeutics 193 16005519
2004 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism. Neuropharmacology 167 15223298
2001 A role for 5-ht6 receptors in retention of spatial learning in the Morris water maze. Neuropharmacology 164 11489457
2007 Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 159 17625499
1999 Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 159 10432491
2007 Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders. Pharmacology & therapeutics 144 18068807
2014 Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer's disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. The Lancet. Neurology 135 25297016
2001 5-HT6 receptor antagonists enhance retention of a water maze task in the rat. Psychopharmacology 127 11702084
2014 Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease. Journal of medicinal chemistry 125 24850589
2006 The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn. The Journal of biological chemistry 124 17189269
2007 Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation. The Journal of neuroscience : the official journal of the Society for Neuroscience 121 17428998
2004 Differential involvement of 5-HT(1B/1D) and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer's disease. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 121 14571255
2005 5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats. Psychopharmacology 101 15846482
2014 Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth. Nature chemical biology 100 24880860
2006 Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients. BMC neuroscience 98 16640790
2010 Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data. Pharmacological reports : PR 97 20884998
1994 5-HT6 receptors positively coupled to adenylyl cyclase in striatal neurones in culture. Neuroreport 95 7696602
1999 Investigation of stretching behaviour induced by the selective 5-HT6 receptor antagonist, Ro 04-6790, in rats. British journal of pharmacology 87 10323584
2007 Pro-cognitive effects of 5-HT6 receptor antagonists in the social recognition procedure in rats: implication of the frontal cortex. Psychopharmacology 86 17922111
2010 E-6801, a 5-HT6 receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission in the rat. Psychopharmacology 85 20405281
2001 Cloning of the mouse 5-HT6 serotonin receptor and mutagenesis studies of the third cytoplasmic loop. Brain research. Molecular brain research 82 11406289
2013 5-HT6 receptors and Alzheimer's disease. Alzheimer's research & therapy 80 23607787
2017 Serotonin 5-HT6 receptors affect cognition in a mouse model of Alzheimer's disease by regulating cilia function. Alzheimer's research & therapy 79 28931427
2005 Oral administration of the 5-HT6 receptor antagonists SB-357134 and SB-399885 improves memory formation in an autoshaping learning task. Pharmacology, biochemistry, and behavior 79 15964617
2016 Physical interaction between neurofibromin and serotonin 5-HT6 receptor promotes receptor constitutive activity. Proceedings of the National Academy of Sciences of the United States of America 74 27791021
1997 Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells. Neuropharmacology 74 9225298
1998 Central distribution and function of 5-HT6 receptor subtype in the rat brain. Life sciences 73 9585121
2018 The role of 5 HT6-receptor antagonists in Alzheimer's disease: an update. Expert opinion on investigational drugs 72 29848076
2006 Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats. British journal of pharmacology 71 16783408
2005 A three-dimensional pharmacophore model for 5-hydroxytryptamine6 (5-HT6) receptor antagonists. Journal of medicinal chemistry 70 15974573
2000 5-ht6 receptors as emerging targets for drug discovery. Annual review of pharmacology and toxicology 70 10836139
2008 Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat. British journal of pharmacology 68 18622410
2011 Influence of social isolation in the rat on serotonergic function and memory--relevance to models of schizophrenia and the role of 5-HT₆ receptors. Neuropharmacology 67 21414329
2002 5-HT6 receptor binding sites in schizophrenia and following antipsychotic drug administration: autoradiographic studies with [125I]SB-258585. Synapse (New York, N.Y.) 67 12112397
1998 Involvement of 5-HT6 receptors in nigro-striatal function in rodents. British journal of pharmacology 67 9884085
2001 Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia. Schizophrenia research 65 11163544
2015 Therapeutic Potential of 5-HT6 Receptor Agonists. Journal of medicinal chemistry 64 26099069
2010 Antidepressant and anxiolytic effects of selective 5-HT6 receptor agonists in rats. Psychopharmacology 64 20217056
2006 Increased expression of 5-HT6 receptors in the rat dorsomedial striatum impairs instrumental learning. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 64 17192775
2010 5-HT6 receptor antagonists as potential therapeutics for cognitive impairment. Current topics in medicinal chemistry 63 20166958
2005 Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands. Journal of medicinal chemistry 63 15771424
2016 Novel 1H-Pyrrolo[3,2-c]quinoline Based 5-HT6 Receptor Antagonists with Potential Application for the Treatment of Cognitive Disorders Associated with Alzheimer's Disease. ACS chemical neuroscience 62 27100049
2015 5-HT6 Receptor Antagonists: Potential Efficacy for the Treatment of Cognitive Impairment in Schizophrenia. Current pharmaceutical design 59 26044973
2014 Novel arylsulfonamide derivatives with 5-HT₆/5-HT₇ receptor antagonism targeting behavioral and psychological symptoms of dementia. Journal of medicinal chemistry 59 24805037
2009 Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities. Biochemical pharmacology 58 19549510
2011 Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats. Neurobiology of learning and memory 57 21757018
2009 The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer's disease. Expert review of neurotherapeutics 54 19589055
2015 Distribution of serotonin receptor 5-HT6 mRNA in rat neuronal subpopulations: A double in situ hybridization study. Neuroscience 53 26424380
2000 Investigation of the human serotonin 6 [5-HT6] receptor gene in bipolar affective disorder and schizophrenia. American journal of medical genetics 53 10893499
2008 5-HT6 receptor antagonists: prospects for the treatment of cognitive disorders including dementia. Current opinion in drug discovery & development 52 18729016
2001 Role of 5-HT6 receptors in memory formation. Drug news & perspectives 50 12813582
2008 Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease. Current topics in medicinal chemistry 49 18691131
2007 5-HT6 receptor antagonist SB-399885 potentiates haloperidol and risperidone-induced dopamine efflux in the medial prefrontal cortex or hippocampus. Brain research 49 17207474
2008 The selective 5-HT6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats. Neuropharmacology 48 18455201
2004 Risperidone response and 5-HT6 receptor gene variance: genetic association analysis with adjustment for nongenetic confounders. Schizophrenia research 48 14741325
2015 5-HT6 Receptor: A New Player Controlling the Development of Neural Circuits. ACS chemical neuroscience 47 25590789
2012 Activation of 5-HT6 receptors modulates sleep-wake activity and hippocampal theta oscillation. ACS chemical neuroscience 47 23336058
2011 5-HT6 receptor memory and amnesia: behavioral pharmacology--learning and memory processes. International review of neurobiology 47 21329783
2011 The 5-HT6 receptor agonist EMD 386088 produces antidepressant and anxiolytic effects in rats after intrahippocampal administration. Psychopharmacology 47 21499701
1994 5-Hydroxytryptamine receptors with a 5-HT6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes. Naunyn-Schmiedeberg's archives of pharmacology 47 7845473
2014 Memory formation and memory alterations: 5-HT6 and 5-HT7 receptors, novel alternative. Reviews in the neurosciences 46 24698823
2006 Efficacy of selective 5-HT6 receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways. British journal of pharmacology 46 16865095
2005 2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists. Bioorganic & medicinal chemistry letters 46 16055331
2008 Prefrontal executive function and D1, D3, 5-HT2A and 5-HT6 receptor gene variations in healthy adults. Journal of psychiatry & neuroscience : JPN 45 18197272
1996 Effects of altered 5-ht6 expression in the rat: functional studies using antisense oligonucleotides. Behavioural brain research 45 8788511
2012 Radiosynthesis and characterization of 11C-GSK215083 as a PET radioligand for the 5-HT6 receptor. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 44 22223878
2010 Benzimidazole derivatives as new serotonin 5-HT6 receptor antagonists. Molecular mechanisms of receptor inactivation. Journal of medicinal chemistry 44 20078106
1999 Association analysis of the 5-HT6 receptor polymorphism C267T in Alzheimer's disease. Neuroscience letters 44 10624811
2007 Memory consolidation and amnesia modify 5-HT6 receptors expression in rat brain: an autoradiographic study. Behavioural brain research 42 17267053
2007 Increased expression of 5-HT6 receptors in the nucleus accumbens blocks the rewarding but not psychomotor activating properties of cocaine. Biological psychiatry 40 17631868
1999 Effects of clozapine and haloperidol on 5-HT6 receptor mRNA levels in rat brain. Schizophrenia research 40 10427606
2015 Investigational drugs targeting 5-HT6 receptors for the treatment of Alzheimer's disease. Expert opinion on investigational drugs 39 26548316
2016 N1-Azinylsulfonyl-1H-indoles: 5-HT6 Receptor Antagonists with Procognitive and Antidepressant-Like Properties. ACS medicinal chemistry letters 38 27326337
2009 Role of peripheral and spinal 5-HT6 receptors according to the rat formalin test. Neuroscience 38 19422883
2005 Association between the 5-HT6 receptor C267T polymorphism and response to antidepressant treatment in major depressive disorder. Psychiatry and clinical neurosciences 38 15823158
2012 5-HT6 receptor blockade differentially affects scopolamine-induced deficits of working memory, recognition memory and aversive learning in mice. Psychopharmacology 37 22367167
2011 Activation of 5-HT6 receptors inhibits corticostriatal glutamatergic transmission. Neuropharmacology 36 21619890
2015 5-HT6 receptor agonism facilitates emotional learning. Frontiers in pharmacology 35 26441657
2011 N'-(arylsulfonyl)pyrazoline-1-carboxamidines as novel, neutral 5-hydroxytryptamine 6 receptor (5-HT₆R) antagonists with unique structural features. Journal of medicinal chemistry 35 21866910
2008 Binding of serotonin and N1-benzenesulfonyltryptamine-related analogs at human 5-HT6 serotonin receptors: receptor modeling studies. Journal of medicinal chemistry 34 18201064
1999 Association study of the 5-HT6 receptor gene in schizophrenia. American journal of medical genetics 34 10206228
1999 Ionotropic glutamate receptor modulation of 5-HT6 and 5-HT7 mRNA expression in rat brain. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34 10457531
2016 Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT4R) partial agonist and 5-HT6R antagonist activities, as potential treatment of Alzheimer's disease. European journal of medicinal chemistry 33 27266998
2014 5-HT6 Receptor Recruitment of mTOR Modulates Seizure Activity in Epilepsy. Molecular neurobiology 33 25034463
2014 The procognitive effects of 5-HT6 receptor ligands in animal models of schizophrenia. Reviews in the neurosciences 32 24501158
2010 (3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: potent and selective antagonists of the serotonin 5-HT6 receptor. Journal of medicinal chemistry 32 20560595
2007 5-HT6 receptor antagonist reversal of emotional learning and prepulse inhibition deficits induced by apomorphine or scopolamine. Pharmacology, biochemistry, and behavior 32 17920665
2019 SUVN-502, a novel, potent, pure, and orally active 5-HT6 receptor antagonist: pharmacological, behavioral, and neurochemical characterization. Behavioural pharmacology 31 29847336
2019 Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement. PLoS biology 31 30883547
2016 The 5-HT6 receptor antagonist idalopirdine potentiates the effects of acetylcholinesterase inhibition on neuronal network oscillations and extracellular acetylcholine levels in the rat dorsal hippocampus. Neuropharmacology 31 27039041
2008 Selective 5-HT6 receptor blockade improves spatial recognition memory and reverses age-related deficits in spatial recognition memory in the mouse. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 31 18596685
2003 Creation, expression, and characterization of a constitutively active mutant of the human serotonin 5-HT6 receptor. Synapse (New York, N.Y.) 31 12494404
1998 Characterization of 5-ht6 receptor and expression of 5-ht6 mRNA in the rat brain during ontogenetic development. Naunyn-Schmiedeberg's archives of pharmacology 30 9606024
1998 The putative 5-ht6 receptor: localization and function. Annals of the New York Academy of Sciences 30 9928244

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