Affinage

HTR1A

5-hydroxytryptamine receptor 1A · UniProt P08908

Length
422 aa
Mass
46.1 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTR1A (5-HT1A) is a Gi/o-coupled serotonin receptor that suppresses neuronal activity, serving both as a somatodendritic autoreceptor on raphe serotonergic neurons and as a postsynaptic heteroreceptor in cortical, hippocampal, and hypothalamic circuits (PMID:10482904, PMID:1973941). The receptor couples to inhibitory G proteins to inhibit adenylyl cyclase, and its activation hyperpolarizes neurons by opening G protein-coupled inwardly rectifying potassium (GIRK) channels (PMID:15306649), reducing the firing of dorsal raphe 5-HT neurons and limiting forebrain 5-HT synthesis (PMID:1973941). Coupling is region-selective — Gi3 in 5-HT neurons versus Gi2 in hippocampal neurons — with Gβγ-driven ion channel modulation reducing excitability and, in hippocampal neurons, additional engagement of ERK1/2 and PI3K/Akt signaling (PMID:31079617). Receptor pharmacology spans full agonism, inverse agonism that stabilizes G-protein-uncoupled or inactive states, and ligand-dependent control of the ternary complex (PMID:1828347, PMID:10617139). Spatial deployment of the receptor is actively controlled: the C-terminus binds the trafficking protein Yif1B, which is required for dendritic targeting (PMID:18685031), while ZDHHC21-mediated palmitoylation supports signaling competence and partitioning into lipid microdomains that promote receptor homo-oligomerization (PMID:31477731, PMID:18853255). Expression is set transcriptionally by Deaf-1/HES1/HES5 repressors acting at the promoter, where the C(-1019)G polymorphism relieves autoreceptor repression and elevates raphe receptor levels (PMID:15534042, PMID:18499474), and by corticosteroid regulation of hippocampal expression (PMID:8441016). Autoreceptor abundance is causally determinative: genetically elevated raphe autoreceptor levels increase firing inhibition, behavioral despair, and antidepressant resistance, whereas autoreceptor knockdown elevates prefrontal 5-HT release and produces antidepressant-like effects (PMID:20152112, PMID:22820867). Beyond neuronal signaling, HTR1A also acts in non-neuronal contexts, stabilizing TGF-β receptor II against proteasomal degradation in breast cancer cells (PMID:35199941) and, in serotonergic and GnRH cell models, regulating gene expression through PI3K/Akt and MAPK/ERK pathways (PMID:34458005).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1990 Medium

    Established the core physiological dichotomy: 5-HT1A acts as a somatodendritic autoreceptor inhibiting raphe firing and 5-HT synthesis, and as a postsynaptic receptor negatively coupled to adenylyl cyclase, defining the receptor's two-compartment role.

    Evidence Electrophysiology of raphe neuron firing, neurochemical 5-HT synthesis assays, and adenylyl cyclase assays

    PMID:1973941

    Open questions at the time
    • Did not resolve which Gi/o isoforms mediate each compartment
    • Mechanism of receptor desensitization not addressed
  2. 1991 Medium

    Demonstrated functional agonist coupling by showing a ligand inhibits forskolin-stimulated adenylate cyclase with GTP-sensitive binding, confirming the Gi-linked cyclase-inhibitory readout in native tissue.

    Evidence Radioligand binding with GTP shift and adenylate cyclase assay in rat hippocampal membranes

    PMID:1828347

    Open questions at the time
    • Single agonist tested in one tissue
    • No downstream pathway beyond cAMP examined
  3. 1993 High

    Revealed that receptor expression is not static but set by endocrine state, with corticosteroids bidirectionally regulating hippocampal 5-HT1A mRNA and binding.

    Evidence In situ hybridization and receptor autoradiography with adrenalectomy and corticosterone replacement in rats

    PMID:8441016

    Open questions at the time
    • Transcription factors mediating corticosteroid effect not identified
    • Effect on raphe autoreceptors versus heteroreceptors not distinguished
  4. 1996 Medium

    Mapped the subcellular distribution underlying the autoreceptor/heteroreceptor distinction, placing the receptor in the somatodendritic compartment of raphe neurons and the axon hillock of pyramidal neurons.

    Evidence Immunocytochemistry with antipeptide antibody in primate brain

    PMID:8719028

    Open questions at the time
    • Trafficking mechanism producing compartment-specific localization unknown
    • Functional consequence of astrocytic expression unaddressed
  5. 1999 High

    Reconstituted the cloned receptor in heterologous cells to define Gi/o coupling, multiple downstream signaling linkages, and desensitization mechanisms independent of neuronal context.

    Evidence Recombinant expression in cell lines, cAMP assays, site-directed mutagenesis

    PMID:10482904

    Open questions at the time
    • Did not map G-protein isoform specificity by neuron type
    • Endogenous neuronal partners not captured in heterologous system
  6. 2000 High

    Distinguished classes of antagonist behavior at the receptor, showing inverse agonists suppress basal G-protein activity and stabilize distinct receptor conformations within the ternary complex.

    Evidence [35S]GTPγS binding in CHO-5-HT1A cells with ternary complex modeling and ion modulation

    PMID:10617139

    Open questions at the time
    • Structural basis of the stabilized conformations not resolved
    • In vivo relevance of constitutive activity untested
  7. 2003 Medium

    Showed that receptor signaling efficiency is regulated by a neurotrophin, as BDNF deficiency reduces 5-HT1A–G protein coupling without altering receptor number.

    Evidence Agonist-stimulated [35S]GTPγS binding autoradiography and radioligand binding in BDNF +/− mice

    PMID:12753073

    Open questions at the time
    • Molecular link between BDNF signaling and coupling efficiency unidentified
    • Behavioral consequence of altered coupling not isolated
  8. 2004 High

    Resolved the ion-channel effector for inhibition, demonstrating 5-HT1A hyperpolarizes target neurons by activating GIRK channels with defined single-channel conductance.

    Evidence Patch-clamp electrophysiology in orexin neurons with selective pharmacology and immunohistochemistry

    PMID:15306649

    Open questions at the time
    • Gβγ versus Gα contribution to channel gating not dissected here
    • Limited to one neuronal population
  9. 2004 Medium

    Demonstrated cross-receptor regulation, with 5-HT2A activation causing heterologous desensitization of co-localized 5-HT1A receptors within single neuroendocrine cells.

    Evidence In vivo neuroendocrine assays with intra-PVN 5-HT2A antagonist microinjection and double-label immunocytochemistry

    PMID:15064330

    Open questions at the time
    • Intracellular signaling mediating cross-desensitization unidentified
    • Restricted to PVN neuroendocrine cells
  10. 2004 Medium

    Identified the transcriptional basis of the disease-associated promoter variant, showing C(-1019)G blocks Deaf-1/Hes repression to raise autoreceptor expression.

    Evidence Promoter-reporter assays and transcription factor binding studies in neuronal cell lines

    PMID:15534042

    Open questions at the time
    • Allele-specific effects on heteroreceptors versus autoreceptors not fully separated
    • In vivo human consequences inferred
  11. 2005 Medium

    Characterized the developmental trajectory of receptor expression, from perinuclear localization in immature neurons to dendritic distribution with maturation, plus transient glial expression.

    Evidence Immunohistochemistry across embryonic to postnatal rat hippocampus

    PMID:15939084

    Open questions at the time
    • Mechanism driving the perinuclear-to-dendritic shift not defined
    • Function of transient glial expression unknown
  12. 2008 High

    Identified Yif1B as the C-terminal-binding trafficking partner required specifically for dendritic targeting, providing a molecular basis for compartment-specific receptor delivery.

    Evidence Yeast two-hybrid, GST pull-down, co-localization, and siRNA knockdown in primary neurons

    PMID:18685031

    Open questions at the time
    • How Yif1B selects 5-HT1A over other cargo unresolved
    • Role in raphe autoreceptor targeting not directly tested
  13. 2008 Medium

    Showed the receptor self-associates into plasma-membrane homo-oligomers and that palmitoylation promotes oligomerization via lipid-microdomain partitioning.

    Evidence Live-cell 2-excitation FRET with CFP/YFP-tagged receptors and palmitoylation-deficient mutant

    PMID:18853255

    Open questions at the time
    • Functional consequence of oligomerization for signaling not established
    • Single-lab live-cell FRET
  14. 2008 High

    Established HES1 as a developmental repressor of receptor transcription required in vivo, acting at a promoter consensus site including the G(-1019) allele, with HES6 relieving repression.

    Evidence Promoter-reporter assays, mutagenesis of HES site, and HES1−/− mouse embryo analysis

    PMID:18499474

    Open questions at the time
    • Adult versus developmental contributions of HES1 not separated
    • Interplay with corticosteroid regulation untested
  15. 2010 High

    Established causality between autoreceptor level and behavior, with genetically elevated raphe autoreceptors increasing firing inhibition, despair, and antidepressant resistance.

    Evidence Genetic mouse models with selective raphe autoreceptor manipulation, electrophysiology, microdialysis, and behavior

    PMID:20152112

    Open questions at the time
    • Did not test acute, reversible manipulation
    • Heteroreceptor contribution held separate but not co-varied
  16. 2012 High

    Confirmed the autoreceptor as a therapeutic lever, showing acute DRN autoreceptor knockdown increases prefrontal 5-HT release and produces antidepressant-like effects that augment fluoxetine.

    Evidence Intra-DRN siRNA, in situ hybridization, microdialysis, and behavioral tests with 5-HT1A KO controls

    PMID:22820867

    Open questions at the time
    • Durability of knockdown effect not assessed
    • Effect on heteroreceptor-mediated responses not measured
  17. 2015 Medium

    Extended autoreceptor function to addiction circuitry, showing DRN 5-HT1A autoreceptors are necessary for cocaine place preference and compulsive self-administration under extended access.

    Evidence 5-HT-neuron-specific conditional knockdown, DREADD stimulation of DRN→NAc projections, rat self-administration

    PMID:26324408

    Open questions at the time
    • Downstream NAc circuit mechanism not resolved
    • Single-lab behavioral model
  18. 2018 Medium

    Resolved region-specific G-protein coupling (Gi3 in 5-HT neurons, Gi2 in hippocampal neurons) and the downstream divergence into ion-channel inhibition versus ERK/PI3K-Akt/CaMKII signaling.

    Evidence Compiled G-protein coupling, signaling pathway assays, and ion channel recordings across neuronal systems

    PMID:31079617

    Open questions at the time
    • Determinants of isoform-selective coupling unknown
    • Synthesized from multiple primary sources
  19. 2019 High

    Identified ZDHHC21 as the palmitoyl acyltransferase controlling receptor signaling competence, linked reduced palmitoylation to MDD pathology and to miR-30e regulation.

    Evidence Palmitoylation assays, ZDHHC21 knockdown, palmitoylation-deficient mutant, post-mortem human cortex, and behavior in forebrain ZDHHC21-knockdown mice

    PMID:31477731

    Open questions at the time
    • Causal direction of palmitoylation changes in human MDD not established
    • Effect on autoreceptor versus heteroreceptor pools not separated
  20. 2019 Medium

    Defined a neuroprotective astrocytic function, with astrocyte 5-HT1A stimulation driving metallothionein upregulation and dopaminergic neuroprotection.

    Evidence Primary astrocyte cultures, conditioned-medium and antibody-neutralization experiments, and 6-OHDA mouse model

    PMID:31765686

    Open questions at the time
    • Signaling pathway from astrocyte 5-HT1A to MT induction not mapped
    • Single-lab pharmacological model
  21. 2021 Medium

    Showed receptor signaling controls epigenetic gene regulation, as HTR1A antagonism upregulates GnRH by destabilizing PRC1/CBX4 and reducing H2AK119 ubiquitination through PI3K/Akt and MAPK/ERK suppression.

    Evidence RNA-seq, ChIP-seq, and Co-IP with WAY-100635 treatment in GT1-7 GnRH neuronal cells

    PMID:34458005

    Open questions at the time
    • In vivo relevance of GnRH regulation untested
    • Single cell line
  22. 2022 Medium

    Uncovered a non-canonical, signaling-independent scaffolding role, with HTR1A binding TRIM21 and PSMD7 to protect TGF-β receptor II from proteasomal degradation in breast cancer.

    Evidence Co-IP, RNA-seq, siRNA knockdown, and in vivo/in vitro breast cancer functional assays

    PMID:35199941

    Open questions at the time
    • Whether G-protein signaling contributes to this role unknown
    • Single-lab cancer model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How transcriptional control, palmitoylation, trafficking, and oligomerization are integrated to set the autoreceptor/heteroreceptor balance in vivo, and how this balance governs antidepressant response in humans, remains unresolved.
  • No unified model linking post-translational and transcriptional control to compartment-specific receptor pools
  • Causal human validation of autoreceptor-level effects on treatment response lacking
  • Structural basis of region-specific G-protein selectivity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
DEAF1HES1HTR7PSMD7TRIM21YIF1BZDHHC21
Complex memberships
5-HT1A homo-oligomer5-HT1A/5-HT7 heterodimer

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 The 5-HT1A receptor couples to inhibitory G proteins (Gi/o) to inhibit adenylyl cyclase; transfection of the cloned receptor cDNA into naive cells revealed multiple signal transduction pathways including novel signaling linkages and elucidated mechanisms of receptor desensitization. Recombinant receptor expression in heterologous cell lines, cAMP/adenylyl cyclase assays, site-directed mutagenesis British journal of pharmacology High 10482904
1991 DMT acts as a full agonist at 5-HT1A receptors, inhibiting forskolin-stimulated adenylate cyclase activity in rat hippocampus with EC50 ~4 µM; GTP sensitivity of radioligand binding confirmed agonist activity. Radioligand binding with GTP shift, adenylate cyclase assay in rat hippocampal membranes Biochemical pharmacology Medium 1828347
2000 Methiothepin and spiperone act as inverse agonists at the 5-HT1A receptor, inhibiting both agonist-stimulated and basal [35S]GTPγS binding in CHO cells expressing the receptor; spiperone stabilizes receptor forms uncoupled from G proteins, while methiothepin stabilizes an inactive receptor form that retains G protein coupling. [35S]GTPγS binding assay in CHO-5-HT1A cells, extended ternary complex model simulation, modulation by GDP and sodium ion concentration Journal of neurochemistry High 10617139
2004 5-HT1A receptors mediate hyperpolarization of orexin/hypocretin neurons via activation of G protein-coupled inward rectifier potassium (GIRK) channels (single-channel conductance ~33.8 pS); 5-HT1A receptor-like immunoreactivity was detected on orexin neurons and serotonergic nerve endings apposed to orexin neurons. Patch-clamp electrophysiology (whole-cell and single-channel) in hypothalamic slices from orexin-EGFP transgenic mice, pharmacological blockade with WAY100635, Ba2+ channel blockade, immunohistochemistry The Journal of neuroscience High 15306649
2008 The intracellular trafficking protein Yif1B interacts with the C-terminal domain of the 5-HT1A receptor and is required for targeting of the receptor to distal dendrites; siRNA knockdown of Yif1B specifically prevented dendritic addressing of 5-HT1A receptor without affecting other receptors (sst2A, P2X2, 5-HT3A). Yeast two-hybrid screen using 5-HT1A C-terminal 17 aa as bait, GST pull-down with rat brain extracts and transfected cell lines, co-localization imaging, siRNA knockdown in primary neuron cultures The Journal of neuroscience High 18685031
1996 5-HT1A receptor immunoreactivity is localized to the somatodendritic compartment (dendritic shaft, branches, spines, perikaryon) of raphe neurons and to the axon hillock of cortical and hippocampal pyramidal neurons; astrocytes and other non-neuronal cells also express the receptor. Immunocytochemistry with antipeptide antibody (aa170-186) in perfusion-fixed primate brain (Macaca fascicularis) Neuropsychopharmacology Medium 8719028
2019 5-HT1A receptor is palmitoylated in human and rodent brains; ZDHHC21 is the major palmitoyl acyltransferase responsible; depletion of ZDHHC21 reduces palmitoylation and signaling functions of 5-HT1AR; miR-30e negatively regulates ZDHHC21 expression; reduced 5-HT1AR palmitoylation and ZDHHC21 expression were found in post-mortem prefrontal cortex of MDD suicides. Palmitoylation assays in brain tissue and cell lines, siRNA knockdown of ZDHHC21, palmitoylation-deficient mutant, microRNA analysis, post-mortem human brain analysis, behavioral assays in mice with forebrain-specific ZDHHC21 knockdown Nature communications High 31477731
2008 5-HT1A receptors form specific homo-oligomers at the plasma membrane of living cells, as demonstrated by FRET between CFP- and YFP-tagged receptors; palmitoylation promotes receptor localization to lipid-rich microdomains and increases effective surface density, thereby facilitating oligomerization — a palmitoylation-deficient mutant showed reduced FRET efficiency. 2-excitation FRET with spectral microscopy in living cells, CFP/YFP-tagged 5-HT1A receptors, palmitoylation-deficient mutant analysis Glycoconjugate journal Medium 18853255
2014 5-HT1A and 5-HT7 receptors form homo- and heterodimers both in vitro and in vivo; heterodimerization plays a role in regulation of receptor-mediated signaling and internalization. Co-immunoprecipitation and FRET-based dimerization assays in vitro and in vivo (as described in cited review citing primary data) CNS neuroscience & therapeutics Low 24935787
2004 5-HT2A receptor activation in the hypothalamic paraventricular nucleus (PVN) induces heterologous desensitization of 5-HT1A receptors within individual neuroendocrine cells; 5-HT1A and 5-HT2A receptors are colocalized in oxytocin and CRF neurons of the PVN; microinjection of 5-HT2A antagonist MDL100,907 prevented desensitization. In vivo neuroendocrine functional assay (oxytocin and ACTH responses to 8-OH-DPAT), microinjection of 5-HT2A antagonist into PVN, double-label immunocytochemistry The Journal of pharmacology and experimental therapeutics Medium 15064330
2010 Mice engineered with higher 5-HT1A autoreceptor levels in raphe nuclei (1A-High) show robustly increased raphe firing rate inhibition, increased behavioral despair, and no behavioral response to antidepressants, establishing a causal relationship between 5-HT1A autoreceptor level, raphe firing, stress resilience, and antidepressant response. Genetic mouse models selectively manipulating raphe 5-HT1A autoreceptors; electrophysiological recording of raphe firing; in vivo microdialysis; behavioral testing; antidepressant response assays Neuron High 20152112
2012 Acute siRNA-mediated knockdown of 5-HT1A autoreceptors in the dorsal raphe nucleus reduces receptor mRNA and binding, abolishes 8-OH-DPAT-induced hypothermia, and increases prefrontal 5-HT release during stress, producing antidepressant-like effects and augmenting fluoxetine-evoked 5-HT release. Stereotaxic intra-DRN siRNA infusion, in situ hybridization, receptor binding, in vivo microdialysis, behavioral tests (tail suspension, forced swim), 8-OH-DPAT-induced hypothermia Psychopharmacology High 22820867
1993 Adrenal corticosteroids selectively regulate hippocampal 5-HT1A receptor expression; adrenalectomy increases 5-HT1A receptor mRNA and binding throughout the hippocampus, and exogenous corticosterone replacement restores levels to sham values. In situ hybridization for 5-HT1A mRNA, in vitro receptor autoradiography with [3H]8-OH-DPAT, adrenalectomy and corticosterone replacement in rats The Journal of neuroscience High 8441016
2004 The C(-1019)G (rs6295) polymorphism in the HTR1A promoter selectively blocks repression by the transcription factors NUDR/Deaf-1, Hes1, and Hes5 at the autoreceptor locus, resulting in increased 5-HT1A autoreceptor expression in raphe neurons. Promoter-reporter assays in neuronal cell lines, transcription factor binding studies, in vitro and in vivo allele-specific repression assays The Neuroscientist Medium 15534042
2008 HES1 strongly represses 5-HT1A receptor transcription via a consensus HES site in the promoter, including at the G(-1019) allele (unlike HES5); HES6 reverses HES1- and HES5-mediated repression; HES1 knockout mice show elevated 5-HT1A receptor RNA and protein in hindbrain and midbrain at E12.5, establishing HES1 as required for correct developmental expression. Promoter-reporter assays in neuronal and non-neuronal cells, site-directed mutagenesis of HES consensus site, HES1−/− mouse embryos analyzed by in situ hybridization and immunohistochemistry Molecular and cellular neurosciences High 18499474
2003 BDNF deficiency (heterozygous BDNF +/− mice) attenuates 5-HT1A receptor-stimulated [35S]GTPγS binding in the median and dorsal raphe nucleus and hippocampus without changing receptor number, indicating that BDNF regulates 5-HT1A receptor–G protein coupling efficiency. Agonist-stimulated [35S]GTPγS binding autoradiography, radioligand binding for receptor number, two-bottle choice ethanol intake in BDNF +/− vs WT mice Journal of neurochemistry Medium 12753073
2021 HTR1A antagonism (WAY-100635) in GT1-7 GnRH neuronal cells upregulates GnRH expression by reducing CBX4 (a PRC1 component) expression, decreasing H2AK119 ubiquitination at the GnRH promoter, and degrading the PRC1 complex; this is mediated through suppression of PI3K/Akt and MAPK/ERK pathways. RNA-seq, ChIP-seq for CBX4 and H2AK119ub, co-immunoprecipitation (RING2, YY1, CBX4 interaction), pharmacological treatment of GT1-7 cells with WAY-100635 Molecular therapy. Nucleic acids Medium 34458005
2022 HTR1A interacts with TRIM21 and PSMD7 to inhibit ubiquitin-proteasome-dependent degradation of TGF-β receptor II (TβRII), thereby suppressing both canonical and noncanonical TGF-β signaling pathways in triple-negative breast cancer cells. Co-immunoprecipitation assays, RNA-seq, siRNA knockdown, in vivo and in vitro functional experiments in breast cancer models Advanced science Medium 35199941
1990 5-HT1A receptor agonists inhibit the firing rate of 5-HT-containing dorsal raphe neurons and inhibit cortical/hippocampal 5-HT synthesis via presynaptic somatodendritic autoreceptors; postsynaptic 5-HT1A receptors are negatively coupled to adenylyl cyclase. Electrophysiology (in vitro and in vivo raphe neuron firing), neurochemical assays of 5-HT synthesis inhibition, adenylyl cyclase functional assays Journal of clinical psychopharmacology Medium 1973941
2018 5-HT1A receptor coupled primarily to Gi3 in 5-HT neurons and to Gi2 in hippocampal neurons; Gβγ subunit-mediated signaling opens potassium channels and closes calcium channels to reduce neuronal activity; in hippocampal neurons (but not 5-HT neurons), 5-HT1A receptor signals to activate ERK1/2 and can also engage ACII, PLC/PKC, CaMKII, and PI3K/Akt pathways through Gβγ and tyrosine kinase receptor crosstalk. G protein coupling studies in neuronal cell lines and primary neurons, signaling pathway assays (ERK, PI3K/Akt, CAMKII), ion channel recordings; review compiling primary experimental data Biochimie Medium 31079617
2015 5-HT1A autoreceptors in the dorsal raphe nucleus are necessary for cocaine conditioned place preference; inhibition of dorsal raphe 5-HT1A autoreceptors attenuates compulsive cocaine self-administration in rats with extended (6 h) but not limited (1 h) access. 5-HT neuron-specific 5-HT1A autoreceptor gene knockdown (conditional KO), DREADD-mediated stimulation of DRN→NAc serotonergic projections, rat cocaine self-administration model Neuropsychopharmacology Medium 26324408
2005 5-HT1A receptor protein expression in the developing rat hippocampus begins at initial stages of embryonic development, is concentrated around cell bodies before distributing to dendrites as neurons mature, and is transiently expressed in S100/GFAP-positive glia during early postnatal development. Immunohistochemistry with validated anti-5-HT1A antibody in developing rat hippocampus from embryonic to early postnatal stages Brain research. Developmental brain research Medium 15939084
2019 Rotigotine stimulates astrocyte 5-HT1A receptors to increase astrocyte proliferation and upregulate metallothionein (MT)-1,2 expression; conditioned medium from rotigotine-treated astrocytes protects dopaminergic neurons from 6-OHDA toxicity; these effects were completely blocked by a 5-HT1A antagonist or MT-1,2 antibody in vitro and in vivo. Primary astrocyte cultures, conditioned medium experiments, 5-HT1A antagonist blockade, MT-1,2 antibody neutralization, subcutaneous rotigotine in 6-OHDA mouse model with immunohistochemistry Neurochemistry international Medium 31765686
1998 Stimulation of postsynaptic (not presynaptic) 5-HT1A receptors impairs passive avoidance retention in rats; the memory deficit is blocked by selective 5-HT1A antagonists but not 5-HT2A/2C antagonists or beta-blockers; 5-HT1A receptor stimulation interferes with both acquisition and retrieval phases of learning. Step-through passive avoidance test in rats, selective pharmacological agonists and antagonists (WAY 100135, ketanserin, alprenolol), state-dependent learning paradigm, tryptophan depletion (PCPA) British journal of pharmacology Medium 9806333

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Is there a role for 5-HT1A agonists in the treatment of depression? Biological psychiatry 440 12559651
1995 5-HT1A receptor agonists: recent developments and controversial issues. Psychopharmacology 414 8539333
2004 The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. Journal of psychiatry & neuroscience : JPN 367 15309042
2010 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron 346 20152112
2007 Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors. Progress in neurobiology 251 17316955
1990 Do functional relationships exist between 5-HT1A and 5-HT2 receptors? Pharmacology, biochemistry, and behavior 238 2145593
1996 Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 225 8719028
2004 5-HT1A receptors, gene repression, and depression: guilt by association. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 221 15534042
1993 Corticosteroids regulate brain hippocampal 5-HT1A receptor mRNA expression. The Journal of neuroscience : the official journal of the Society for Neuroscience 211 8441016
1999 The recombinant 5-HT1A receptor: G protein coupling and signalling pathways. British journal of pharmacology 209 10482904
2001 Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models. Neurology 200 11723272
2001 The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics? Journal of psychopharmacology (Oxford, England) 183 11277607
2010 5-HT1A receptor-regulated signal transduction pathways in brain. Cellular signalling 181 20363322
1993 Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents. Trends in pharmacological sciences 176 8122313
2003 Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration. Life sciences 163 12559389
2018 The 5-HT1A receptor: Signaling to behavior. Biochimie 161 31079617
2004 Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 161 15306649
2016 The 5-HT1A receptor in Major Depressive Disorder. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 158 26851834
2008 Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Neuropharmacology 141 18639564
2003 5-HT1A receptor knockout mouse as a genetic model of anxiety. European journal of pharmacology 136 12600709
2004 Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology. The international journal of neuropsychopharmacology 126 15469667
2011 Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness. Molecular brain 121 21619616
2009 Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety. Archives of general psychiatry 120 19124686
1991 5-HT1A receptor responsivity in anxiety disorders and depression. Progress in neuro-psychopharmacology & biological psychiatry 120 1763190
2012 Transcriptional regulation of the 5-HT1A receptor: implications for mental illness. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 119 22826341
2010 The importance of 5-HT1A receptor agonism in antipsychotic drug action: rationale and perspectives. Current opinion in investigational drugs (London, England : 2000) 114 20571976
2003 Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (+/-) mice. Journal of neurochemistry 114 12753073
2000 5-HT1A and beyond: the role of serotonin and its receptors in depression and the antidepressant response. Human psychopharmacology 110 12404340
1996 The 5-HT1A receptor: signaling, desensitization, and gene transcription. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 104 8719026
1999 Anxiety and increased 5-HT1A receptor response in NCAM null mutant mice. Journal of neurobiology 103 10440734
1994 5-HT1A receptor sensitivity in major depression. A neuroendocrine study with buspirone. The British journal of psychiatry : the journal of mental science 95 8199791
2014 Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders. CNS neuroscience & therapeutics 94 24935787
2019 Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors. Nature communications 93 31477731
2007 Serotonin-1A receptor gene HTR1A variation predicts interferon-induced depression in chronic hepatitis C. Gastroenterology 84 17408646
1994 5-HT1A receptor influences on rodent social and agonistic behavior: a review and empirical study. Neuroscience and biobehavioral reviews 84 7984351
1992 5-HT1A receptor-effector system responsivity in panic disorder. Psychopharmacology 83 1346719
2015 Hippocampal 5-HT1A Receptor and Spatial Learning and Memory. Frontiers in pharmacology 82 26696889
2009 Effect of 5-HT1A gene polymorphisms on antidepressant response in major depressive disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 82 18484082
2004 Decreased 5-HT1A receptor binding in amygdala of schizophrenia. Biological psychiatry 82 15023569
2007 Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression. Journal of neural transmission (Vienna, Austria : 1996) 76 17401528
2008 5-HT1A receptor, an old target for new therapeutic agents. Current topics in medicinal chemistry 74 18691130
2004 Desensitization of 5-HT1A receptors by 5-HT2A receptors in neuroendocrine neurons in vivo. The Journal of pharmacology and experimental therapeutics 69 15064330
2004 Focus on The 5-HT1A receptor: emerging role of a gene regulatory variant in psychopathology and pharmacogenetics. The international journal of neuropsychopharmacology 68 15683551
2005 5-HT1A receptor expression in pyramidal neurons of cortical and limbic brain regions. Cell and tissue research 66 15947971
2007 HTR2C and HTR1A gene variants in German and Italian suicide attempters and completers. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 64 17192951
1994 Antiemetic effects of serotonergic 5-HT1A-receptor agonists in Suncus murinus. Japanese journal of pharmacology 64 8028227
2012 Acute 5-HT₁A autoreceptor knockdown increases antidepressant responses and serotonin release in stressful conditions. Psychopharmacology 59 22820867
1990 Neurochemistry and neurophysiology of buspirone and gepirone: interactions at presynaptic and postsynaptic 5-HT1A receptors. Journal of clinical psychopharmacology 58 1973941
2008 Targeting of the 5-HT1A serotonin receptor to neuronal dendrites is mediated by Yif1B. The Journal of neuroscience : the official journal of the Society for Neuroscience 56 18685031
2005 Ontogeny of 5-HT1A receptor expression in the developing hippocampus. Brain research. Developmental brain research 56 15939084
1991 Differential interactions of dimethyltryptamine (DMT) with 5-HT1A and 5-HT2 receptors. Biochemical pharmacology 54 1828347
1999 The 5-HT1A receptor and its ligands: structure and function. Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques 53 10396127
1997 Effect of paroxetine and nefazodone on 5-HT1A receptor sensitivity. Psychopharmacology 52 9292630
2000 Mechanisms of agonism and inverse agonism at serotonin 5-HT1A receptors. Journal of neurochemistry 51 10617139
1997 5-HT1A-versus D2-receptor selectivity of flesinoxan and analogous N4-substituted N1-arylpiperazines. Journal of medicinal chemistry 50 9022796
1998 Analysis of the 5-HT1A receptor involvement in passive avoidance in the rat. British journal of pharmacology 49 9806333
2016 Evaluation of association of common variants in HTR1A and HTR5A with schizophrenia and executive function. Scientific reports 47 27897266
2005 The 5-HT1A receptor and the stimulus effects of LSD in the rat. Psychopharmacology 47 16025319
1999 Androgens and estrogens modulate 5-HT1A and 5-HT1B agonist effects on aggression. Physiology & behavior 47 10073487
1996 New 5-HT1A receptor antagonist: [3H]p-MPPF. Synapse (New York, N.Y.) 47 8855520
1993 Prenatal developmental expression of rat brain 5-HT1A receptor gene followed by PCR. Biochemical and biophysical research communications 45 8466538
2019 Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm. Journal of psychiatry & neuroscience : JPN 44 30807072
2015 5-HT1A Receptor-Mediated Autoinhibition and the Control of Serotonergic Cell Firing. ACS chemical neuroscience 44 25913021
2010 Brainstem changes in 5-HT1A receptor availability during migraine attack. Cephalalgia : an international journal of headache 44 21036859
2004 Occupancy of agonist drugs at the 5-HT1A receptor. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 44 14985704
2015 5-HT1A Autoreceptors in the Dorsal Raphe Nucleus Convey Vulnerability to Compulsive Cocaine Seeking. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 41 26324408
2013 The 5-HT1A receptor and 5-HT transporter in temporal lobe epilepsy. Neurology 40 23516322
1990 Influence of 5-HT1A receptor agonists on sympathetic and parasympathetic nerve activity. Journal of cardiovascular pharmacology 39 1702490
2017 HTR1A/1B DNA methylation may predict escitalopram treatment response in depressed Chinese Han patients. Journal of affective disorders 38 29275155
2010 The HTR1A and HTR1B receptor genes influence stress-related information processing. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 38 20638825
2005 5-HT1A receptor expression during memory formation. Psychopharmacology 38 15778876
2003 Opioid hyperalgesia and tolerance versus 5-HT1A receptor-mediated inverse tolerance. Trends in pharmacological sciences 37 14654304
2011 Presynaptic 5-HT1A is related to 5-HTT receptor density in the human brain. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 36 21750580
2009 Memory time-course: mRNA 5-HT1A and 5-HT7 receptors. Behavioural brain research 36 19447286
2005 Role of 5-HT1A and 5-HT1B receptors in the antinociceptive effect of tramadol. European journal of pharmacology 36 15777775
1996 Development of 5-HT1A receptor antagonists. Behavioural brain research 36 8788494
2008 Serotonin receptor HTR1A and HTR2C variants and personality traits in suicide attempters and controls. Journal of psychiatric research 35 18715570
2019 Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors: Possibly involvement of metallothionein expression in astrocytes. Neurochemistry international 34 31765686
2008 Association study between the serotonin 1A receptor (HTR1A) gene and neuroticism, major depression, and anxiety disorders. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 34 18163385
2014 The functional -1019C/G HTR1A polymorphism and mechanisms of fear. Translational psychiatry 33 25514753
1989 Involvement of brain 5-HT1A receptors in the hypotensive response to urapidil. The American journal of cardiology 33 2569265
2012 The therapeutic potential of 5-HT1A receptors: a patent review. Expert opinion on therapeutic patents 31 22788968
2010 Regulation of cortical and striatal 5-HT1A receptors in the MPTP-lesioned macaque. Neurobiology of aging 31 21051107
2015 TREK1 channel blockade induces an antidepressant-like response synergizing with 5-HT1A receptor signaling. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 30 26441141
2010 Panic disorder and serotonergic genes (SLC6A4, HTR1A and HTR2A): Association and interaction with childhood trauma and parenting. Neuroscience letters 30 20817074
2003 Effect of fentanyl on 5-HT efflux involves both opioid and 5-HT1A receptors. British journal of pharmacology 30 12922937
2021 The epigenetic role of HTR1A antagonist in facilitaing GnRH expression for pubertal initiation control. Molecular therapy. Nucleic acids 29 34458005
1991 Structure-activity relationships at 5-HT1A receptors: binding profiles and intrinsic activity. Pharmacology, biochemistry, and behavior 29 1816558
2008 HES1 regulates 5-HT1A receptor gene transcription at a functional polymorphism: essential role in developmental expression. Molecular and cellular neurosciences 28 18499474
2000 Modulation of 5-HT1A receptor mediated response by fluoxetine in rat brain. Journal of neural transmission (Vienna, Austria : 1996) 28 10821446
1991 The 5-HT1A receptor: an overview of recent advances. Neurochemical research 27 2052135
2013 Activation of postsynaptic 5-HT1A receptors improve stress adaptation. Psychopharmacology 26 24258351
1994 Anxiolytic and antidepressant mechanisms of 5-HT1A drugs in the pigeon: contributions from behavioral studies. Neuroscience and biobehavioral reviews 26 7909594
2018 5-HT1A receptor ligands and their therapeutic applications: review of new patents. Expert opinion on therapeutic patents 25 30124346
2014 Stress-induced alterations in 5-HT1A receptor transcriptional modulators NUDR and Freud-1. The international journal of neuropsychopharmacology 25 24946016
2022 HTR1A Inhibits the Progression of Triple-Negative Breast Cancer via TGF-β Canonical and Noncanonical Pathways. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 24 35199941
2008 Specific oligomerization of the 5-HT1A receptor in the plasma membrane. Glycoconjugate journal 24 18853255
2018 5-HT1A Receptor Function Makes Wound Healing a Happier Process. Frontiers in pharmacology 23 30618734
2014 PET radiotracers for molecular imaging of serotonin 5-HT1A receptors. Current medicinal chemistry 23 23992341
2005 Treatment of cerebellar ataxia with 5-HT1A agonist. Cerebellum (London, England) 23 16147954

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