5-HT1A receptor

{{short description|Serotonin receptor protein distributed in the cerebrum and raphe nucleus}} {{DISPLAYTITLE:5-HT1A receptor}} {{Infobox gene}}

The '''serotonin 1A receptor''' (or '''5-HT1A receptor''') is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.<ref name="pmid2591972">{{cite journal | vauthors = Gilliam TC, Freimer NB, Kaufmann CA, Powchik PP, Bassett AS, Bengtsson U, Wasmuth JJ | title = Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia | journal = Genomics | volume = 5 | issue = 4 | pages = 940–4 | date = November 1989 | pmid = 2591972 | pmc = 3154173 | doi = 10.1016/0888-7543(89)90138-9 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: HTR1A 5-hydroxytryptamine (serotonin) receptor 1A | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=3350 }}</ref>

== Distribution ==

The 5-HT1A receptor is the most widespread of all the 5-HT receptors. In the central nervous system, 5-HT1A receptors exist in the cerebral cortex, hippocampus, septum, amygdala, and raphe nucleus in high densities, while low amounts also exist in the basal ganglia and thalamus.<ref name="pmid9935065">{{cite journal | vauthors = Ito H, Halldin C, Farde L | title = Localization of 5-HT1A receptors in the living human brain using [carbonyl-11C]WAY-100635: PET with anatomic standardization technique | journal = Journal of Nuclear Medicine | volume = 40 | issue = 1 | pages = 102–9 | date = January 1999 | pmid = 9935065 }}</ref><ref name="urlSerotonin Receptor Subtypes and Ligands">{{cite web | url = http://www.acnp.org/g4/GN401000039/Ch039.html | title = Serotonin Receptor Subtypes and Ligands | access-date = 2008-04-11 | vauthors = Glennon RA, Dukat M, Westkaemper RB | date = 2000-01-01 | publisher = American College of Neurophyscopharmacology | archive-url= https://web.archive.org/web/20080421160353/http://www.acnp.org/g4/GN401000039/Ch039.html| archive-date= 21 April 2008 | url-status= live}}</ref><ref name="pmid18761712">{{cite journal | vauthors = de Almeida J, Mengod G | title = Serotonin 1A receptors in human and monkey prefrontal cortex are mainly expressed in pyramidal neurons and in a GABAergic interneuron subpopulation: implications for schizophrenia and its treatment | journal = Journal of Neurochemistry | volume = 107 | issue = 2 | pages = 488–96 | date = October 2008 | pmid = 18761712 | doi = 10.1111/j.1471-4159.2008.05649.x | s2cid = 23783438 | doi-access = free }}</ref> The 5-HT1A receptors in the raphe nucleus are largely somatodendritic autoreceptors, whereas those in other areas such as the hippocampus are postsynaptic receptors.<ref name="urlSerotonin Receptor Subtypes and Ligands"/>

== Function ==

=== Neuromodulation ===

5-HT1A receptor agonists are involved in neuromodulation. They decrease blood pressure and heart rate via a central mechanism, by inducing peripheral vasodilation, and by stimulating the vagus nerve.<ref name="pmid1819150">{{cite journal | vauthors = Dabiré H | title = Central 5-hydroxytryptamine (5-HT) receptors in blood pressure regulation | journal = Therapie | volume = 46 | issue = 6 | pages = 421–9 | year = 1991 | pmid = 1819150 }}</ref> These effects are the result of activation of 5-HT1A receptors within the rostral ventrolateral medulla.<ref name="pmid1819150"/> The sympatholytic antihypertensive drug urapidil is an α1-adrenergic receptor antagonist and 5-HT1A receptor agonist, and it has been demonstrated that the latter property contributes to its overall therapeutic effects.<ref name="pmid1855130">{{cite journal | vauthors = Ramage AG | title = The mechanism of the sympathoinhibitory action of urapidil: role of 5-HT1A receptors | journal = British Journal of Pharmacology | volume = 102 | issue = 4 | pages = 998–1002 | date = April 1991 | pmid = 1855130 | pmc = 1917978 | doi = 10.1111/j.1476-5381.1991.tb12290.x }}</ref><ref name="pmid2569265">{{cite journal | vauthors = Kolassa N, Beller KD, Sanders KH | title = Involvement of brain 5-HT1A receptors in the hypotensive response to urapidil | journal = The American Journal of Cardiology | volume = 64 | issue = 7 | pages = 7D–10D | date = August 1989 | pmid = 2569265 | doi = 10.1016/0002-9149(89)90688-7 }}</ref> Vasodilation of the blood vessels in the skin via central 5-HT1A activation increases heat dissipation from the organism out into the environment, causing a decrease in body temperature.<ref name="pmid16455061">{{cite journal | vauthors = Ootsuka Y, Blessing WW | title = Activation of 5-HT1A receptors in rostral medullary raphé inhibits cutaneous vasoconstriction elicited by cold exposure in rabbits | journal = Brain Research | volume = 1073–1074 | pages = 252–61 | date = February 2006 | pmid = 16455061 | doi = 10.1016/j.brainres.2005.12.031 | s2cid = 23178233 }}</ref><ref name="pmid17702902">{{cite journal | vauthors = Rusyniak DE, Zaretskaia MV, Zaretsky DV, DiMicco JA | title = 3,4-Methylenedioxymethamphetamine- and 8-hydroxy-2-di-n-propylamino-tetralin-induced hypothermia: role and location of 5-hydroxytryptamine 1A receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 323 | issue = 2 | pages = 477–87 | date = November 2007 | pmid = 17702902 | doi = 10.1124/jpet.107.126169 | s2cid = 14197613 }}</ref>

Activation of central 5-HT1A receptors triggers the release or inhibition of norepinephrine depending on species, presumably from the locus coeruleus, which then reduces or increases neuronal tone to the iris sphincter muscle by modulation of postsynaptic α2-adrenergic receptors within the Edinger-Westphal nucleus, resulting in pupil dilation in rodents, and pupil constriction in primates including humans.<ref name="pmid15087245">{{cite journal | vauthors = Yu Y, Ramage AG, Koss MC | title = Pharmacological studies of 8-OH-DPAT-induced pupillary dilation in anesthetized rats | journal = European Journal of Pharmacology | volume = 489 | issue = 3 | pages = 207–13 | date = April 2004 | pmid = 15087245 | doi = 10.1016/j.ejphar.2004.03.007 }}</ref><ref name="pmid8982715">{{cite journal | vauthors = Prow MR, Martin KF, Heal DJ | title = 8-OH-DPAT-induced mydriasis in mice: a pharmacological characterisation | journal = European Journal of Pharmacology | volume = 317 | issue = 1 | pages = 21–8 | date = December 1996 | pmid = 8982715 | doi = 10.1016/S0014-2999(96)00693-0 }}</ref><ref name="pmid7697953">{{cite journal | vauthors = Fanciullacci M, Sicuteri R, Alessandri M, Geppetti P | title = Buspirone, but not sumatriptan, induces miosis in humans: relevance for a serotoninergic pupil control | journal = Clinical Pharmacology and Therapeutics | volume = 57 | issue = 3 | pages = 349–55 | date = March 1995 | pmid = 7697953 | doi = 10.1016/0009-9236(95)90161-2 | s2cid = 24512607 }}</ref>

5-HT1A receptor agonists like buspirone<ref>{{cite journal | vauthors = Cohn JB, Rickels K | title = A pooled, double-blind comparison of the effects of buspirone, diazepam and placebo in women with chronic anxiety | journal = Current Medical Research and Opinion | volume = 11 | issue = 5 | pages = 304–20 | year = 1989 | pmid = 2649317 | doi = 10.1185/03007998909115213 }}</ref> and flesinoxan<ref name="pmid9169298">{{cite journal | vauthors = Cryan JF, Redmond AM, Kelly JP, Leonard BE | title = The effects of the 5-HT1A agonist flesinoxan, in three paradigms for assessing antidepressant potential in the rat | journal = European Neuropsychopharmacology | volume = 7 | issue = 2 | pages = 109–14 | date = May 1997 | pmid = 9169298 | doi = 10.1016/S0924-977X(96)00391-4 | s2cid = 42048881 }}</ref> show efficacy in relieving anxiety<ref name="pmid9724773">{{cite journal | vauthors = Parks CL, Robinson PS, Sibille E, Shenk T, Toth M | title = Increased anxiety of mice lacking the serotonin1A receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 18 | pages = 10734–9 | date = September 1998 | pmid = 9724773 | pmc = 27964 | doi = 10.1073/pnas.95.18.10734 | bibcode = 1998PNAS...9510734P | doi-access = free }}</ref> and depression.<ref name="pmid2883013">{{cite journal | vauthors = Kennett GA, Dourish CT, Curzon G | title = Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression | journal = European Journal of Pharmacology | volume = 134 | issue = 3 | pages = 265–74 | date = February 1987 | pmid = 2883013 | doi = 10.1016/0014-2999(87)90357-8 }}</ref> Buspirone, tandospirone, and gepirone are currently approved for these indications in different parts of the world.<ref name="pmid15643103">{{cite journal | vauthors = Keller MB, Ruwe FJ, Janssens CJ, Sitsen JM, Jokinen R, Janczewski J | title = Relapse prevention with gepirone ER in outpatients with major depression | journal = Journal of Clinical Psychopharmacology | volume = 25 | issue = 1 | pages = 79–84 | date = February 2005 | pmid = 15643103 | doi = 10.1097/01.jcp.0000150221.53877.d9 | s2cid = 72677194 }}</ref> Others such as flesinoxan,<ref name="pmid9169298" /> flibanserin,<ref>{{cite journal | vauthors = Invernizzi RW, Sacchetti G, Parini S, Acconcia S, Samanin R | title = Flibanserin, a potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT(1A) receptors | journal = British Journal of Pharmacology | volume = 139 | issue = 7 | pages = 1281–8 | date = August 2003 | pmid = 12890707 | pmc = 1573953 | doi = 10.1038/sj.bjp.0705341 | url = }}</ref> and naluzotan<ref name="pmid17263189">{{cite journal | vauthors = de Paulis T | title = Drug evaluation: PRX-00023, a selective 5-HT1A receptor agonist for depression | journal = Current Opinion in Investigational Drugs | volume = 8 | issue = 1 | pages = 78–86 | date = January 2007 | pmid = 17263189 }}</ref> have also been investigated, though none have been fully developed and approved yet. Some of the atypical antipsychotics like lurasidone<ref name="pmid27722855">{{cite journal | vauthors = Greenberg WM, Citrome L | title = Pharmacokinetics and Pharmacodynamics of Lurasidone Hydrochloride, a Second-Generation Antipsychotic: A Systematic Review of the Published Literature | journal = Clinical Pharmacokinetics | volume = 56 | issue = 5 | pages = 493–503 | date = May 2017 | pmid = 27722855 | doi = 10.1007/s40262-016-0465-5 | url = https://touroscholar.touro.edu/nymc_fac_pubs/462 | s2cid = 207485482 | url-access = subscription }}</ref> and aripiprazole<ref name="pmid17242925">{{cite journal | vauthors = Stark AD, Jordan S, Allers KA, Bertekap RL, Chen R, Mistry Kannan T, Molski TF, Yocca FD, Sharp T, Kikuchi T, Burris KD | display-authors = 6 | title = Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT 2A receptors: functional receptor-binding and in vivo electrophysiological studies | journal = Psychopharmacology | volume = 190 | issue = 3 | pages = 373–82 | date = February 2007 | pmid = 17242925 | doi = 10.1007/s00213-006-0621-y | s2cid = 25349673 }}</ref> are also partial agonists at the 5-HT1A receptor and are sometimes used in low doses as augmentations to standard antidepressants like the selective serotonin reuptake inhibitors (SSRIs).<ref>{{cite journal | vauthors = Wheeler Vega JA, Mortimer AM, Tyson PJ | title = Conventional antipsychotic prescription in unipolar depression, I: an audit and recommendations for practice | journal = The Journal of Clinical Psychiatry | volume = 64 | issue = 5 | pages = 568–74 | date = May 2003 | pmid = 12755661 | doi = 10.4088/JCP.v64n0512 | url = http://www.psychiatrist.com/abstracts/abstracts.asp?abstract=200305/050311.htm | url-status = live | archive-url = https://web.archive.org/web/20090620064725/http://www.psychiatrist.com/abstracts/abstracts.asp?abstract=200305%2F050311.htm | archive-date = 20 June 2009 | url-access = subscription }}</ref> Mice lacking 5-HT1A receptors altogether (knockout) show increased anxiety but lower depressive-like behaviour.<ref>{{cite journal | vauthors = Donaldson ZR, Nautiyal KM, Ahmari SE, Hen R | title = Genetic approaches for understanding the role of serotonin receptors in mood and behavior | journal = Current Opinion in Neurobiology | volume = 23 | issue = 3 | pages = 399–406 | date = June 2013 | pmid = 23385115 | pmc = 3652904 | doi = 10.1016/j.conb.2013.01.011 }}</ref>

5-HT1A autoreceptor desensitization and increased 5-HT1A receptor postsynaptic activation via general increases in serotonin levels by serotonin precursor supplementation, serotonin reuptake inhibition, or inhibition of monoamine oxidase has been shown to be a major mediator in the therapeutic benefits of most mainstream antidepressant supplements and pharmaceuticals, including serotonin precursors like L-tryptophan and 5-HTP, SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), and monoamine oxidase inhibitors (MAOIs).<ref name="pmid11212592">{{cite journal | vauthors = Blier P, Abbott FV | title = Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain | journal = Journal of Psychiatry & Neuroscience | volume = 26 | issue = 1 | pages = 37–43 | date = January 2001 | pmid = 11212592 | pmc = 1408043 | url = http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-26/issue-1/pdf/pg37.pdf | access-date = 2009-07-05 | url-status = dead | archive-url = https://web.archive.org/web/20160306214237/https://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-26/issue-1/pdf/pg37.pdf | archive-date = 2016-03-06 }}</ref> 5-HT1A receptor activation likely plays a significant role in the positive effects of serotonin releasing agents (SRAs) like MDMA (commonly known as ecstasy) as well.<ref name="pmid15908091">{{cite journal | vauthors = Morley KC, Arnold JC, McGregor IS | title = Serotonin (1A) receptor involvement in acute 3,4-methylenedioxymethamphetamine (MDMA) facilitation of social interaction in the rat | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 29 | issue = 5 | pages = 648–57 | date = June 2005 | pmid = 15908091 | doi = 10.1016/j.pnpbp.2005.04.009 | s2cid = 24451268 }}</ref><ref name="pmid17383105">{{cite journal | vauthors = Thompson MR, Callaghan PD, Hunt GE, Cornish JL, McGregor IS | title = A role for oxytocin and 5-HT(1A) receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine ("ecstasy") | journal = Neuroscience | volume = 146 | issue = 2 | pages = 509–14 | date = May 2007 | pmid = 17383105 | doi = 10.1016/j.neuroscience.2007.02.032 | s2cid = 15617471 }}</ref>

5-HT1A receptors in the dorsal raphe nucleus are co-localized with neurokinin 1 (NK1) receptors and have been shown to inhibit the release of substance P, their endogenous ligand.<ref name="pmid16950604">{{cite journal|author1-link=Gabriella Gobbi | vauthors = Gobbi G, Cassano T, Radja F, Morgese MG, Cuomo V, Santarelli L, Hen R, Blier P | display-authors = 6 | title = Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function | journal = European Neuropsychopharmacology | volume = 17 | issue = 5 | pages = 328–38 | date = April 2007 | pmid = 16950604 | doi = 10.1016/j.euroneuro.2006.07.004 | s2cid = 24350120 }}</ref><ref>{{cite journal | vauthors = Baker KG, Halliday GM, Hornung JP, Geffen LB, Cotton RG, Törk I | title = Distribution, morphology and number of monoamine-synthesizing and substance P-containing neurons in the human dorsal raphe nucleus | journal = Neuroscience | volume = 42 | issue = 3 | pages = 757–75 | year = 1991 | pmid = 1720227 | doi = 10.1016/0306-4522(91)90043-N | s2cid = 23034680 }}</ref> In addition to being antidepressant and anxiolytic in effect, 5-HT1A receptor activation has also been demonstrated to be antiemetic<ref name="pmid8013549">{{cite journal | vauthors = Lucot JB | title = Antiemetic effects of flesinoxan in cats: comparisons with 8-hydroxy-2-(di-n-propylamino)tetralin | journal = European Journal of Pharmacology | volume = 253 | issue = 1–2 | pages = 53–60 | date = February 1994 | pmid = 8013549 | doi = 10.1016/0014-2999(94)90756-0 }}</ref><ref name="pmid12401641">{{cite journal | vauthors = Oshima T, Kasuya Y, Okumura Y, Terazawa E, Dohi S | title = Prevention of nausea and vomiting with tandospirone in adults after tympanoplasty | journal = Anesthesia and Analgesia | volume = 95 | issue = 5 | pages = 1442–5, table of contents | date = November 2002 | pmid = 12401641 | doi = 10.1097/00000539-200211000-00063 | url = http://www.anesthesia-analgesia.org/cgi/pmidlookup?view=long&pmid=12401641 | s2cid = 26108853 | doi-access = free }}</ref> and analgesic,<ref name="pmid12595749">{{cite journal | vauthors = Bardin L, Tarayre JP, Malfetes N, Koek W, Colpaert FC | title = Profound, non-opioid analgesia produced by the high-efficacy 5-HT(1A) agonist F 13640 in the formalin model of tonic nociceptive pain | journal = Pharmacology | volume = 67 | issue = 4 | pages = 182–94 | date = April 2003 | pmid = 12595749 | doi = 10.1159/000068404 | s2cid = 25882138 }}</ref><ref name="pmid16425670">{{cite journal | vauthors = Colpaert FC | title = 5-HT(1A) receptor activation: new molecular and neuroadaptive mechanisms of pain relief | journal = Current Opinion in Investigational Drugs | volume = 7 | issue = 1 | pages = 40–7 | date = January 2006 | pmid = 16425670 }}</ref> and all of these properties may be mediated in part or full, depending on the property in question, by NK1 receptor inhibition. Consequently, novel NK1 receptor antagonists are now in use for the treatment of nausea and emesis, and are also being investigated for the treatment of anxiety and depression.<ref name="pmid15173897">{{cite journal | vauthors = Blier P, Gobbi G, Haddjeri N, Santarelli L, Mathew G, Hen R | title = Impact of substance P receptor antagonism on the serotonin and norepinephrine systems: relevance to the antidepressant/anxiolytic response | journal = Journal of Psychiatry & Neuroscience | volume = 29 | issue = 3 | pages = 208–18 | date = May 2004 | pmid = 15173897 | pmc = 400690 }}</ref>

5-HT1A receptor activation has been shown to increase dopamine release in the medial prefrontal cortex, striatum, and hippocampus, and may be useful for improving the symptoms of schizophrenia and Parkinson's disease.<ref name="pmid 11238736">{{cite journal | vauthors = Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O'Laughlin IA, Meltzer HY | title = 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release | journal = Journal of Neurochemistry | volume = 76 | issue = 5 | pages = 1521–1531 | date = December 2001 | pmid = 11238736 | doi = 10.1046/j.1471-4159.2001.00154.x }}</ref> As mentioned above, some of the atypical antipsychotics are 5-HT1A receptor partial agonists, and this property has been shown to enhance their clinical efficacy.<ref name="pmid15189766">{{cite journal | vauthors = Li Z, Ichikawa J, Dai J, Meltzer HY | title = Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in rat brain | journal = European Journal of Pharmacology | volume = 493 | issue = 1–3 | pages = 75–83 | date = June 2004 | pmid = 15189766 | doi = 10.1016/j.ejphar.2004.04.028 }}</ref><ref name="pmid10924666">{{cite journal | vauthors = Rollema H, Lu Y, Schmidt AW, Sprouse JS, Zorn SH | title = 5-HT(1A) receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex | journal = Biological Psychiatry | volume = 48 | issue = 3 | pages = 229–37 | date = August 2000 | pmid = 10924666 | doi = 10.1016/S0006-3223(00)00850-7 | s2cid = 54398705 }}</ref><ref name="pmid9456005">{{cite journal | vauthors = Rollema H, Lu Y, Schmidt AW, Zorn SH | title = Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation | journal = European Journal of Pharmacology | volume = 338 | issue = 2 | pages = R3-5 | date = November 1997 | pmid = 9456005 | doi = 10.1016/S0014-2999(97)81951-6 }}</ref> Enhancement of dopamine release in these areas may also play a major role in the antidepressant and anxiolytic effects as seen upon postsynaptic activation of the 5-HT1A receptor.<ref name="pmid11792466">{{cite journal | vauthors = Yoshino T, Nisijima K, Katoh S, Yui K, Nakamura M | title = Tandospirone potentiates the fluoxetine-induced increases in extracellular dopamine via 5-HT(1A) receptors in the rat medial frontal cortex | journal = Neurochemistry International | volume = 40 | issue = 4 | pages = 355–60 | date = April 2002 | pmid = 11792466 | doi = 10.1016/S0197-0186(01)00079-1 | s2cid = 41740125 }}</ref><ref name="pmid1681449">{{cite journal | vauthors = Chojnacka-Wójcik E, Tatarczyńska E, Gołembiowska K, Przegaliński E | title = Involvement of 5-HT1A receptors in the antidepressant-like activity of gepirone in the forced swimming test in rats | journal = Neuropharmacology | volume = 30 | issue = 7 | pages = 711–7 | date = July 1991 | pmid = 1681449 | doi = 10.1016/0028-3908(91)90178-E | s2cid = 46082801 }}</ref>

The activation of 5-HT1A receptors has been demonstrated to impair certain aspects of memory (affecting declarative and non-declarative memory functions) and learning (due to interference with memory-encoding mechanisms), by inhibiting the release of glutamate and acetylcholine in various areas of the brain.<ref name="pmid18394726">{{cite journal | vauthors = Ogren SO, Eriksson TM, Elvander-Tottie E, D'Addario C, Ekström JC, Svenningsson P, Meister B, Kehr J, Stiedl O | display-authors = 6 | title = The role of 5-HT(1A) receptors in learning and memory | journal = Behavioural Brain Research | volume = 195 | issue = 1 | pages = 54–77 | date = December 2008 | pmid = 18394726 | doi = 10.1016/j.bbr.2008.02.023 | s2cid = 140205386 }}</ref> 5-HT1A activation is known to improve cognitive functions associated with the prefrontal cortex, possibly via inducing prefrontal cortex dopamine and acetylcholine release.<ref>{{cite journal | vauthors = Meltzer HY, Sumiyoshi T | title = Does stimulation of 5-HT(1A) receptors improve cognition in schizophrenia? | journal = Behavioural Brain Research | volume = 195 | issue = 1 | pages = 98–102 | date = December 2008 | pmid = 18707769 | doi = 10.1016/j.bbr.2008.05.016 | s2cid = 18455503 }}</ref> Conversely, the 5-HT1A antagonist, WAY100635, alleviated learning and memory impairments induced by glutamate blockade (with dizocilpine)<ref>{{cite journal | vauthors = Harder JA, Ridley RM | title = The 5-HT1A antagonist, WAY 100 635, alleviates cognitive impairments induced by dizocilpine (MK-801) in monkeys | journal = Neuropharmacology | volume = 39 | issue = 4 | pages = 547–52 | date = February 2000 | pmid = 10728875 | doi = 10.1016/s0028-3908(99)00179-3 | s2cid = 43303149 }}</ref> or hippocampal cholinergic denervation (by fornix transection)<ref>{{cite journal | vauthors = Harder JA, Maclean CJ, Alder JT, Francis PT, Ridley RM | title = The 5-HT1A antagonist, WAY 100635, ameliorates the cognitive impairment induced by fornix transection in the marmoset | journal = Psychopharmacology | volume = 127 | issue = 3 | pages = 245–54 | date = October 1996 | pmid = 8912403 | doi = 10.1007/bf02246133 | s2cid = 10132368 }}</ref> in primates. Furthermore, 5-HT1A receptor antagonists such as lecozotan have been shown to facilitate certain types of learning and memory in rodents, and as a result, are being developed as novel treatments for Alzheimer's disease.<ref>{{cite journal | vauthors = Spreitzer H | date = August 13, 2008 | title = Neue Wirkstoffe - Lecozotan | journal = Österreichische Apothekerzeitung | issue = 17/2007 | pages = 805 | language = de }}</ref>

Other effects of 5-HT1A activation that have been observed in scientific research include: * Decreased aggression<ref name="pmid16310183">{{cite journal | vauthors = de Boer SF, Koolhaas JM | title = 5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis | journal = European Journal of Pharmacology | volume = 526 | issue = 1–3 | pages = 125–39 | date = December 2005 | pmid = 16310183 | doi = 10.1016/j.ejphar.2005.09.065 }}</ref><ref name="pmid2091890">{{cite journal | vauthors = Olivier B, Mos J, Rasmussen D | title = Behavioural pharmacology of the serenic, eltoprazine | journal = Drug Metabolism and Drug Interactions | volume = 8 | issue = 1–2 | pages = 31–83 | year = 1990 | pmid = 2091890 | doi = 10.1515/DMDI.1990.8.1-2.31 | s2cid = 27279453 }}</ref> * Increased sociability<ref name="pmid17383105"/> * Decreased impulsivity<ref name="pmid15688093">{{cite journal | vauthors = Winstanley CA, Theobald DE, Dalley JW, Robbins TW | title = Interactions between serotonin and dopamine in the control of impulsive choice in rats: therapeutic implications for impulse control disorders | journal = Neuropsychopharmacology | volume = 30 | issue = 4 | pages = 669–82 | date = April 2005 | pmid = 15688093 | doi = 10.1038/sj.npp.1300610 | doi-access = free }}</ref> * Inhibition of drug-seeking behavior<ref name="pmid7862892">{{cite journal | vauthors = Tomkins DM, Higgins GA, Sellers EM | title = Low doses of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH DPAT) increase ethanol intake | journal = Psychopharmacology | volume = 115 | issue = 1–2 | pages = 173–9 | date = June 1994 | pmid = 7862892 | doi = 10.1007/BF02244769 | s2cid = 38012716 }}</ref><ref name="pmid17316955">{{cite journal | vauthors = Müller CP, Carey RJ, Huston JP, De Souza Silva MA | title = Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors | journal = Progress in Neurobiology | volume = 81 | issue = 3 | pages = 133–78 | date = February 2007 | pmid = 17316955 | doi = 10.1016/j.pneurobio.2007.01.001 | s2cid = 42788995 }}</ref><ref name="pmid15713268">{{cite journal | vauthors = Carey RJ, DePalma G, Damianopoulos E, Shanahan A, Müller CP, Huston JP | title = Evidence that the 5-HT1A autoreceptor is an important pharmacological target for the modulation of cocaine behavioral stimulant effects | journal = Brain Research | volume = 1034 | issue = 1–2 | pages = 162–71 | date = February 2005 | pmid = 15713268 | doi = 10.1016/j.brainres.2004.12.012 | s2cid = 28356741 }}</ref> * Facilitation of sex drive and arousal<ref name="pmid8981617">{{cite journal | vauthors = Fernández-Guasti A, Rodríguez-Manzo G | title = 8-OH-DPAT and male rat sexual behavior: partial blockade by noradrenergic lesion and sexual exhaustion | journal = Pharmacology, Biochemistry, and Behavior | volume = 56 | issue = 1 | pages = 111–6 | date = January 1997 | pmid = 8981617 | doi = 10.1016/S0091-3057(96)00165-7 | s2cid = 26063338 }}</ref><ref name="pmid9228408">{{cite journal | vauthors = Haensel SM, Slob AK | title = Flesinoxan: a prosexual drug for male rats | journal = European Journal of Pharmacology | volume = 330 | issue = 1 | pages = 1–9 | date = July 1997 | pmid = 9228408 | doi = 10.1016/S0014-2999(97)00170-2 }}</ref> * Inhibition of penile erection<ref name="pmid1357709">{{cite journal | vauthors = Simon P, Guardiola B, Bizot-Espiard J, Schiavi P, Costentin J | title = 5-HT1A receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists | journal = Psychopharmacology | volume = 108 | issue = 1–2 | pages = 47–50 | year = 1992 | pmid = 1357709 | doi = 10.1007/BF02245284 | s2cid = 22385029 }}</ref><ref name="pmid9085055">{{cite journal | vauthors = Millan MJ, Perrin-Monneyron S | title = Potentiation of fluoxetine-induced penile erections by combined blockade of 5-HT1A and 5-HT1B receptors | journal = European Journal of Pharmacology | volume = 321 | issue = 3 | pages = R11-3 | date = March 1997 | pmid = 9085055 | doi = 10.1016/S0014-2999(97)00050-2 }}</ref> * Diminished food intake<ref name="pmid17609739">{{cite journal | vauthors = Ebenezer IS, Arkle MJ, Tite RM | title = 8-Hydroxy-2-(di-n-propylamino)-tetralin inhibits food intake in fasted rats by an action at 5-HT1A receptors | journal = Methods and Findings in Experimental and Clinical Pharmacology | volume = 29 | issue = 4 | pages = 269–72 | date = May 2007 | pmid = 17609739 | doi = 10.1358/mf.2007.29.4.1075362 }}</ref> * Prolongation of REM sleep latency<ref name="pmid10607047">{{cite journal | vauthors = Monti JM, Jantos H | title = Dose-dependent effects of the 5-HT1A receptor agonist 8-OH-DPAT on sleep and wakefulness in the rat | journal = Journal of Sleep Research | volume = 1 | issue = 3 | pages = 169–175 | date = September 1992 | pmid = 10607047 | doi = 10.1111/j.1365-2869.1992.tb00033.x | s2cid = 27917774 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ansseau M, Pitchot W, Gonzalez Moreno A, Wauthy J, Papart P | title = Pilot study of flesinoxan, a 5-HT1A agonist, in major depression: Effects on sleep REM latency and body temperature | journal = Human Psychopharmacology: Clinical and Experimental | volume = 8 | issue = 4 | pages = 279–283 | year = 2004 | url = http://www3.interscience.wiley.com/journal/109710934/abstract | archive-url = https://archive.today/20121217194410/http://www3.interscience.wiley.com/journal/109710934/abstract | url-status = dead | archive-date = 2012-12-17 | doi = 10.1002/hup.470080407 | s2cid = 145758823 }}</ref> * Reversal of opioid-induced respiratory depression<ref name="pmid16166206">{{cite journal | vauthors = Meyer LC, Fuller A, Mitchell D | title = Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 290 | issue = 2 | pages = R405-13 | date = February 2006 | pmid = 16166206 | doi = 10.1152/ajpregu.00440.2005 | s2cid = 224414 }}</ref>

=== Endocrinology ===

5-HT1A receptor activation induces the secretion of various hormones including cortisol, corticosterone, adrenocorticotropic hormone (ACTH), oxytocin, prolactin, growth hormone, and β-endorphin.<ref name="pmid9678651">{{cite journal | vauthors = Van de Kar LD, Levy AD, Li Q, Brownfield MS | title = A comparison of the oxytocin and vasopressin responses to the 5-HT1A agonist and potential anxiolytic drug alnespirone (S-20499) | journal = Pharmacology, Biochemistry, and Behavior | volume = 60 | issue = 3 | pages = 677–83 | date = July 1998 | pmid = 9678651 | doi = 10.1016/S0091-3057(98)00025-2 | s2cid = 27817530 }}</ref><ref name="pmid2952898">{{cite journal | vauthors = Lorens SA, Van de Kar LD | title = Differential effects of serotonin (5-HT1A and 5-HT2) agonists and antagonists on renin and corticosterone secretion | journal = Neuroendocrinology | volume = 45 | issue = 4 | pages = 305–10 | date = April 1987 | pmid = 2952898 | doi = 10.1159/000124754 }}</ref><ref name="pmid2956114">{{cite journal | vauthors = Koenig JI, Gudelsky GA, Meltzer HY | title = Stimulation of corticosterone and beta-endorphin secretion in the rat by selective 5-HT receptor subtype activation | journal = European Journal of Pharmacology | volume = 137 | issue = 1 | pages = 1–8 | date = May 1987 | pmid = 2956114 | doi = 10.1016/0014-2999(87)90175-0 }}</ref><ref name="pmid15013031">{{cite journal | vauthors = Pitchot W, Wauthy J, Legros JJ, Ansseau M | title = Hormonal and temperature responses to flesinoxan in normal volunteers: an antagonist study | journal = European Neuropsychopharmacology | volume = 14 | issue = 2 | pages = 151–5 | date = March 2004 | pmid = 15013031 | doi = 10.1016/S0924-977X(03)00108-1 | s2cid = 19082134 }}</ref> The receptor does not affect vasopressin or renin secretion, unlike the 5-HT2 receptors.<ref name="pmid9678651"/><ref name="pmid2952898"/> It has been suggested that oxytocin release may contribute to the prosocial, antiaggressive, and anxiolytic properties observed upon activation of the receptor.<ref name="pmid17383105"/> β-Endorphin secretion may contribute to antidepressant, anxiolytic, and analgesic effects.<ref name="pmid18725263">{{cite journal | vauthors = Navinés R, Martín-Santos R, Gómez-Gil E, Martínez de Osaba MJ, Gastó C | title = Interaction between serotonin 5-HT1A receptors and beta-endorphins modulates antidepressant response | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 32 | issue = 8 | pages = 1804–9 | date = December 2008 | pmid = 18725263 | doi = 10.1016/j.pnpbp.2008.07.021 | s2cid = 37943722 }}</ref>

=== Autoreceptors ===

5-HT1A receptors can be located on the cell body, dendrites, axons, and both presynaptically and postsynaptically in nerve terminals or synapses. Those located on the soma and dendrites are referred to as somatodendritic, and those located presynaptically in the synapse are simply referred to as presynaptic. As a group, receptors that are sensitive to the neurotransmitter that is released by the neuron on which the receptors are located are known as autoreceptors; they typically constitute the key component of an ultra-short negative feedback loop whereby the neuron's release of neurotransmitter inhibits its further release of neurotransmitter. Stimulation of 5-HT1A autoreceptors inhibits the release of serotonin in nerve terminals. For this reason, 5-HT1A receptor agonists tend to exert a biphasic mode of action; they decrease serotonin release and postsynaptic 5-HT1A receptor activity in low doses, and further decrease serotonin release but increase postsynaptic 5-HT1A receptor activity at higher doses by directly stimulating the receptors in place of serotonin.

This autoreceptor-mediated inhibition of serotonin release has been theorized to be a major factor in the therapeutic lag that is seen with serotonergic antidepressants such as the SSRIs.<ref name="pmid10890313">{{cite journal | vauthors = Hjorth S, Bengtsson HJ, Kullberg A, Carlzon D, Peilot H, Auerbach SB | title = Serotonin autoreceptor function and antidepressant drug action | journal = Journal of Psychopharmacology | volume = 14 | issue = 2 | pages = 177–85 | date = June 2000 | pmid = 10890313 | doi = 10.1177/026988110001400208 | s2cid = 33440228 }}</ref> The autoreceptors must first desensitize before the concentration of extracellular serotonin in the synapse can become elevated appreciably.<ref name="pmid10890313"/><ref name="pmid8221701">{{cite journal | vauthors = Briley M, Moret C | title = Neurobiological mechanisms involved in antidepressant therapies | journal = Clinical Neuropharmacology | volume = 16 | issue = 5 | pages = 387–400 | date = October 1993 | pmid = 8221701 | doi = 10.1097/00002826-199310000-00002 }}</ref> Though the responsiveness of the autoreceptors is somewhat reduced with chronic treatment, they still remain effective at constraining large increases in extracellular serotonin concentrations.<ref name="pmid10890313"/> For this reason, serotonin reuptake inhibitors that also have 5-HT1A receptor antagonistic or partial agonistic properties, such as vilazodone and SB-649,915, are being investigated and introduced as novel antidepressants with the potential for a faster onset of action and improved effectiveness compared to those currently available.<ref name="pmid17356576">{{cite journal | vauthors = Starr KR, Price GW, Watson JM, Atkinson PJ, Arban R, Melotto S, Dawson LA, Hagan JJ, Upton N, Duxon MS | display-authors = 6 | title = SB-649915-B, a novel 5-HT1A/B autoreceptor antagonist and serotonin reuptake inhibitor, is anxiolytic and displays fast onset activity in the rat high light social interaction test | journal = Neuropsychopharmacology | volume = 32 | issue = 10 | pages = 2163–72 | date = October 2007 | pmid = 17356576 | doi = 10.1038/sj.npp.1301341 | doi-access = free }}</ref>

Unlike most drugs that elevate extracellular serotonin levels like the SSRIs and MAOIs, SRAs such as fenfluramine and MDMA bypass serotonin autoreceptors such as 5-HT1A. They do this by directly acting on the release mechanisms of serotonin neurons and forcing release to occur regardless of autoreceptor-mediated inhibition.<ref name="pmid17017961">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–59 | year = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 | url = http://www.bentham-direct.org/pages/content.php?CTMC/2006/00000006/00000017/0004R.SGM | access-date = 2019-04-30 | url-status = usurped | archive-url = https://web.archive.org/web/20170326103021/http://www.bentham-direct.org/pages/content.php?CTMC%2F2006%2F00000006%2F00000017%2F0004R.SGM | archive-date = 2017-03-26 | url-access = subscription }}</ref> As such, SRAs induce immediate and much greater increases in extracellular serotonin concentrations compared to other serotonin-elevating agents such as the SSRIs. [Note: This is questionable as the level of serotonin output from SRAs is still dose dependant and, while SRAs will initially bypass autoreceptors, the increase in serotonin they induce will then agonise autoreceptors.] In contrast to SRAs, SSRIs may decrease serotonin levels initially (especially at lower dosages due to the biphasic mode of action mentioned above) and require several weeks of chronic dosing before serotonin concentrations reach their maximal elevation (due to 1A autoreceptor desensitization) and full clinical benefits for conditions such as depression and anxiety are seen<ref name="pmid10428424">{{cite journal | vauthors = Scorza C, Silveira R, Nichols DE, Reyes-Parada M | title = Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action | journal = Neuropharmacology | volume = 38 | issue = 7 | pages = 1055–61 | date = July 1999 | pmid = 10428424 | doi = 10.1016/S0028-3908(99)00023-4 | s2cid = 13714807 }}</ref><ref name="pmid9694528">{{cite journal | vauthors = Marona-Lewicka D, Nichols DE | title = Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents | journal = Psychopharmacology | volume = 138 | issue = 1 | pages = 67–75 | date = July 1998 | pmid = 9694528 | doi = 10.1007/s002130050646 | url = http://link.springer.de/link/service/journals/00213/bibs/8138001/81380067.htm | access-date = 2009-07-05 | url-status = dead | s2cid = 32698247 | archive-url = https://web.archive.org/web/20020112064653/http://link.springer.de/link/service/journals/00213/bibs/8138001/81380067.htm | archive-date = 2002-01-12 | url-access = subscription }}</ref> (although other studies show an acute increase in 5-HT<ref name="pmid8007758">{{cite journal | vauthors = Fuller RW | title = Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis | journal = Life Sciences | volume = 55 | issue = 3 | pages = 163–7 | date = 1994 | pmid = 8007758 | doi = 10.1016/0024-3205(94)00876-0 }}</ref><ref name="pmid7685386">{{cite journal | vauthors = Rutter JJ, Auerbach SB | title = Acute uptake inhibition increases extracellular serotonin in the rat forebrain | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 265 | issue = 3 | pages = 1319–24 | date = June 1993 | pmid = 7685386 | doi = | url = }}</ref> which may account for initial worsening of symptoms in sensitive individuals<ref name="pmid18463627">{{cite journal | vauthors = Bigos KL, Pollock BG, Aizenstein HJ, Fisher PM, Bies RR, Hariri AR | title = Acute 5-HT reuptake blockade potentiates human amygdala reactivity | journal = Neuropsychopharmacology | volume = 33 | issue = 13 | pages = 3221–5 | date = December 2008 | pmid = 18463627 | pmc = 2858321 | doi = 10.1038/npp.2008.52 }}</ref>). For these reasons, selective serotonin releasing agents (SSRAs) such as MDAI and MMAI have been proposed as novel antidepressants with a putatively faster onset of action and improved effectiveness compared to current treatments.<ref name="pmid10428424"/>

Similarly to SRAs, sufficiently high doses of 5-HT1A receptor agonists also bypass the 5-HT1A autoreceptor-mediated inhibition of serotonin release and therefore increase 5-HT1A postsynaptic receptor activation by directly agonizing the postsynaptic receptors in lieu of serotonin.

==Ligands== The distribution of 5-HT1A receptors in the human brain may be imaged with the positron emission tomography using the radioligand [11C] WAY-100,635.<ref name="pmid7498295">{{cite journal | vauthors = Pike VW, McCarron JA, Lammerstma AA, Hume SP, Poole K, Grasby PM, Malizia A, Cliffe IA, Fletcher A, Bench CJ | display-authors = 6 | title = First delineation of 5-HT1A receptors in human brain with PET and [11C]WAY-100635 | journal = European Journal of Pharmacology | volume = 283 | issue = 1–3 | pages = R1-3 | date = September 1995 | pmid = 7498295 | doi = 10.1016/0014-2999(95)00438-Q }}</ref> For example, one study has found increased 5-HT1A binding in type 2 diabetes.<ref name="pmid11814436">{{cite journal | vauthors = Price JC, Kelley DE, Ryan CM, Meltzer CC, Drevets WC, Mathis CA, Mazumdar S, Reynolds CF | display-authors = 6 | title = Evidence of increased serotonin-1A receptor binding in type 2 diabetes: a positron emission tomography study | journal = Brain Research | volume = 927 | issue = 1 | pages = 97–103 | date = February 2002 | pmid = 11814436 | doi = 10.1016/S0006-8993(01)03297-8 | s2cid = 32547663 }}</ref> Another PET study found a negative correlation between the amount of 5-HT1A binding in the raphe nuclei, hippocampus and neocortex and a self-reported tendency to have spiritual experiences.<ref name="pmid14594742">{{cite journal | vauthors = Borg J, Andrée B, Soderstrom H, Farde L | title = The serotonin system and spiritual experiences | journal = The American Journal of Psychiatry | volume = 160 | issue = 11 | pages = 1965–9 | date = November 2003 | pmid = 14594742 | doi = 10.1176/appi.ajp.160.11.1965 | s2cid = 5911066 }}</ref> Labeled with tritium, WAY-100,635 may also be used in autoradiography.<ref name="pmid9152998">{{cite journal | vauthors = Burnet PW, Eastwood SL, Harrison PJ | title = [3H]WAY-100635 for 5-HT1A receptor autoradiography in human brain: a comparison with [3H]8-OH-DPAT and demonstration of increased binding in the frontal cortex in schizophrenia | journal = Neurochemistry International | volume = 30 | issue = 6 | pages = 565–74 | date = June 1997 | pmid = 9152998 | doi = 10.1016/S0197-0186(96)00124-6 | s2cid = 21135585 }}</ref>

===Agonists===

====Partial agonists==== {{div col|colwidth=15em}} * 2C-B<ref name="ManzoniRay2010">{{cite journal | vauthors = Ray TS | title = Psychedelics and the human receptorome | journal = PLOS ONE | volume = 5 | issue = 2 |article-number=e9019 | date = February 2010 | pmid = 20126400 | pmc = 2814854 | doi = 10.1371/journal.pone.0009019 | bibcode = 2010PLoSO...5.9019R | doi-access = free }}</ref> * 2C-E<ref name="ManzoniRay2010"/> * 2C-T-2<ref name="ManzoniRay2010"/> * 4C-T-2<ref name="ManzoniRay2010"/> * 5-CT * 5-MT * 5-MeO-DiPT<ref name="ManzoniRay2010"/> * 5-MeO-DMT * 5-MeO-MiPT<ref name="ManzoniRay2010"/> * 5-MeO-TMT<ref name="ManzoniRay2010"/> * 6-F-DMT<ref name="ManzoniRay2010"/> * Adatanserin * αET * Amphetamine {{citation needed|date=February 2017}} * αMT * Aripiprazole * Asenapine * Bacoside * Bay R 1531 * Befiradol * Binospirone * Brexpiprazole * Bufotenin * Buspirone * Cannabidiol<ref>{{cite journal | vauthors = Russo EB, Burnett A, Hall B, Parker KK | title = Agonistic properties of cannabidiol at 5-HT1a receptors | journal = Neurochemical Research | volume = 30 | issue = 8 | pages = 1037–43 | date = August 2005 | pmid = 16258853 | doi = 10.1007/s11064-005-6978-1 | s2cid = 207222631 }}</ref> * Cariprazine * Clozapine * ''cis''-LSZ<ref name="ManzoniRay2010"/> * Dihydroergotamine * Dimethyltryptamine * DiPT<ref name="ManzoniRay2010"/> * DOET<ref name="ManzoniRay2010"/> * DOI<ref name="ManzoniRay2010"/> * DPT<ref name="ManzoniRay2010"/> * Ebalzotan * Eltoprazine * EMDT<ref name="ManzoniRay2010"/> * Ergotamine * Etoperidone * F-11,461 * F-12,826 * F-13,714 * F-14,679 * Flesinoxan * Flibanserin * Ginkgo biloba<ref>{{cite journal | vauthors = Winter JC, Timineri D | title = The discriminative stimulus properties of EGb 761, an extract of Ginkgo biloba | journal = Pharmacology, Biochemistry, and Behavior | volume = 62 | issue = 3 | pages = 543–7 | date = March 1999 | pmid = 10080249 | doi = 10.1016/S0091-3057(98)00190-7 | s2cid = 23055772 }}</ref> * Gepirone * Haloperidol * Lamotrigine * Ipsapirone * Limonene * Lisuride * Lurasidone * LY-301,317 * Lysergic acid diethylamide (LSD) * Mescaline<ref name="ManzoniRay2010"/> * 3,4-Methylenedioxyamphetamine (MDA)<ref name="ManzoniRay2010"/> * 3,4-Methylenedioxymethamphetamine (MDMA)<ref>{{Cite journal|last=Oeri|first=HE|date=2020|title=Beyond ecstasy: alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy|journal=Journal of Psychopharmacology|volume=35|issue=5|pages=512–536|doi=10.1177/0269881120920420|pmid=32909493|pmc=8155739|doi-access=free}}</ref> * Methylphenidate * Methysergide * Naluzotan * NBUMP * Nefazodone * Olanzapine * Osemozotan * Perospirone * Pyrimidinylpiperazine * Piclozotan * Psilocin * Psilocybin * Quetiapine * Rauwolscine * Roxindole * RR-2B<ref name="ManzoniRay2010"/> * RU-24,969 * S-15,535 * Sarizotan * SS-2C<ref name="ManzoniRay2010"/> * SSR-181,507 * Sunepitron * Tandospirone * Tiospirone * Trazodone * Trifluoromethylphenylpiperazine * Trimethoxyamphetamine<ref name="ManzoniRay2010"/> * Umespirone * Urapidil * Vilazodone * Vortioxetine * Xaliproden * Yohimbine<ref name="pmid8517875">{{cite journal | vauthors = Arthur JM, Casañas SJ, Raymond JR | title = Partial agonist properties of rauwolscine and yohimbine for the inhibition of adenylyl cyclase by recombinant human 5-HT1A receptors | journal = Biochemical Pharmacology | volume = 45 | issue = 11 | pages = 2337–41 | date = June 1993 | pmid = 8517875 | doi = 10.1016/0006-2952(93)90208-E }}</ref><ref name="pmid6136920">{{cite journal | vauthors = Kaumann AJ | title = Yohimbine and rauwolscine inhibit 5-hydroxytryptamine-induced contraction of large coronary arteries of calf through blockade of 5 HT2 receptors | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 323 | issue = 2 | pages = 149–54 | date = June 1983 | pmid = 6136920 | doi = 10.1007/BF00634263 | s2cid = 23251900 }}</ref><ref name="pmid8032658">{{cite journal | vauthors = Baxter GS, Murphy OE, Blackburn TP | title = Further characterization of 5-hydroxytryptamine receptors (putative 5-HT2B) in rat stomach fundus longitudinal muscle | journal = British Journal of Pharmacology | volume = 112 | issue = 1 | pages = 323–31 | date = May 1994 | pmid = 8032658 | pmc = 1910288 | doi = 10.1111/j.1476-5381.1994.tb13072.x }}</ref><ref>{{cite web|url=http://www.inchem.org/documents/pims/pharm/yohimbin.htm |title=Yohimbine (PIM 567) |publisher=Inchem.org |access-date=2013-05-26}}</ref> * Zalospirone * Ziprasidone {{Div col end}}

====Full agonists==== {{div col|colwidth=15em}} * 8-OH-DPAT<ref>{{cite journal | vauthors = Winsauer PJ, Rodriguez FH, Cha AE, Moerschbaecher JM | title = Full and partial 5-HT1A receptor agonists disrupt learning and performance in rats | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 288 | issue = 1 | pages = 335–47 | date = January 1999 | pmid = 9862788 | url = http://jpet.aspetjournals.org/content/288/1/335.full.pdf }}</ref> * [https://pubchem.ncbi.nlm.nih.gov/compound/9935515 A-74283] * Alnespirone * Buspirone (presynaptic 5-HT1A) * Befiradol * Tetrahydrocannabivarin (THCV) * Eptapirone * Lesopitron * MKC-242 * LY-293,284 * Osemozotan (presynaptic 5-HT1A) * Repinotan * U-92,016-A * Flibanserin * Vortioxetine {{Div col end}}

====Biased agonists==== * F-15,599 (NLX-101) – ERK1/2-preferring agonist * HBK-17 – β-arrestin biased agonist<ref name="pmid30410441">{{cite journal | vauthors = Pytka K, Głuch-Lutwin M, Żmudzka E, Sałaciak K, Siwek A, Niemczyk K, Walczak M, Smolik M, Olczyk A, Gałuszka A, Śmieja J, Filipek B, Sapa J, Kołaczkowski M, Pańczyk K, Waszkielewicz A, Marona H | display-authors = 6 | title = 1A Receptor Ligand With Anxiolytic-Like Activity, Preferentially Activates ß-Arrestin Signaling | journal = Frontiers in Pharmacology | volume = 9 | pages = 1146 | date = 2018 | pmid = 30410441 | pmc = 6209770 | doi = 10.3389/fphar.2018.01146 | doi-access = free }}</ref> * NLX-204 – ERK1/2 preferring agonist<ref name="pmid30721053">{{cite journal | vauthors = Sniecikowska J, Gluch-Lutwin M, Bucki A, Więckowska A, Siwek A, Jastrzebska-Wiesek M, Partyka A, Wilczyńska D, Pytka K, Pociecha K, Cios A, Wyska E, Wesołowska A, Pawłowski M, Varney MA, Newman-Tancredi A, Kolaczkowski M | display-authors = 6 | title = 1A Receptor-Biased Agonists with Robust Antidepressant-like Activity | journal = Journal of Medicinal Chemistry | volume = 62 | issue = 5 | pages = 2750–2771 | date = March 2019 | pmid = 30721053 | doi = 10.1021/acs.jmedchem.9b00062 | doi-access = free }}</ref> * NLX-266 – ERK1/2 preferring agonist<ref name="SniecikowskaGluch-LutwinBucki2025">{{cite journal | vauthors = Sniecikowska J, Gluch-Lutwin M, Bucki A, Gryzlo B, Wieckowski K, Godyn J, Wieckowska A, Siwek A, Jastrzebska-Wiesek M, Partyka A, Cios A, Wesolowska A, Newman-Tancredi A, Kolaczkowski M | title = Discovery of NLX-266, an Orally Available and Metabolically Stable ERK1/2-Biased 5-HT1AR Agonist with Superior Antidepressant and Antiparkinsonian Activity | journal = J Med Chem | volume = 68 | issue = 9 | pages = 9706–9722 | date = May 2025 | pmid = 40267318 | pmc = 12067441 | doi = 10.1021/acs.jmedchem.5c00484 | url = }}</ref> * TMU4142 – GoA-biased over Gi3 and β-arrestin2<ref name="WangZhangShao2025">{{cite journal | vauthors = Wang C, Zhang N, Shao Y, Li T, Zhang M, Gao M, Liang Y, Wang Y, Xue T, Shi Y, Chen H, Cao C | title = Pathway-selective 5-HT1AR agonist as a rapid antidepressant strategy | journal = Cell | volume = | issue = | pages = | date = November 2025 | pmid = 41232528 | doi = 10.1016/j.cell.2025.10.022 | url = }}</ref>

===Antagonists=== {{div col|colwidth=15em}} * Alprenolol * Alverine * AV-965 * AZD3676 <ref>Varnäs K, Juréus A, Johnström P, Ahlgren C, Schött P, Schou M, Gruber S, Jerning E, Malmborg J, Halldin C, Afzelius L, Farde L. Integrated Strategy for Use of Positron Emission Tomography in Nonhuman Primates to Confirm Multitarget Occupancy of Novel Psychotropic Drugs: An Example with AZD3676. ''J Pharmacol Exp Ther''. 2016 Sep;358(3):464-71. {{doi|10.1124/jpet.116.234146}} {{pmid|27402278}}</ref> * Binospirone (postsynaptic 5-HT1A) * BMY-7,378 * Cannabigerol * Cyanopindolol * Cyproheptadine * Dotarizine * DU-125530 <ref>Scorza MC, Lladó-Pelfort L, Oller S, Cortés R, Puigdemont D, Portella MJ, Pérez-Egea R, Alvarez E, Celada P, Pérez V, Artigas F. Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment. ''Br J Pharmacol''. 2012 Nov;167(5):1021-34. {{doi|10.1111/j.1476-5381.2011.01770.x}} {{pmid|22050051}}</ref> * Flopropione * GSK-588045 (mixed 5-HT1A/B/D antagonist)<ref>Bromidge SM, Arban R, Bertani B, Bison S, Borriello M, Cavanni P, Dal Forno G, Di-Fabio R, Donati D, Fontana S, Gianotti M, Gordon LJ, Granci E, Leslie CP, Moccia L, Pasquarello A, Sartori I, Sava A, Watson JM, Worby A, Zonzini L, Zucchelli V. Design and synthesis of novel tricyclic benzoxazines as potent 5-HT(1A/B/D) receptor antagonists leading to the discovery of 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045). ''J Med Chem''. 2010 Aug 12;53(15):5827-43. {{doi|10.1021/jm100482n}} {{pmid|20590088}}</ref> * GSK-958108 * GR-46,611 * Iodocyanopindolol * Isamoltane * Lecozotan * LY-426965 <ref>Rasmussen K, Calligaro DO, Czachura JF, Dreshfield-Ahmad LJ, Evans DC, Hemrick-Luecke SK, Kallman MJ, Kendrick WT, Leander JD, Nelson DL, Overshiner CD, Wainscott DB, Wolff MC, Wong DT, Branchek TA, Zgombick JM, Xu YC. The novel 5-Hydroxytryptamine(1A) antagonist LY426965: effects on nicotine withdrawal and interactions with fluoxetine. ''J Pharmacol Exp Ther''. 2000 Aug;294(2):688-700. {{pmid|10900249}}</ref> * Mefway * Methiothepin * MM-77 <ref>Alfredo BA, Ofir P. Effect of the postsynaptic 5-HT1A receptor antagonist MM-77 on stressed mice treated with 5-HT1A receptor agents. ''Eur J Pharmacol''. 2005 Jan 31;508(1-3):155-8. {{doi|10.1016/j.ejphar.2004.12.013}} {{pmid|15680266}}</ref> * MPPF * NAN-190 * Nebivolol<ref>{{cite journal | vauthors = Ignarro LJ | title = Different pharmacological properties of two enantiomers in a unique beta-blocker, nebivolol | journal = Cardiovascular Therapeutics | volume = 26 | issue = 2 | pages = 115–34 | date = June 2008 | pmid = 18485134 | doi = 10.1111/j.1527-3466.2008.00044.x | doi-access = free }}</ref> * Oxprenolol * p-MPPI <ref>Kung HF, Kung MP, Clarke W, Maayani S, Zhuang ZP. A potential 5-HT1A receptor antagonist: p-MPPI. ''Life Sci''. 1994;55(19):1459-62. {{doi|10.1016/0024-3205(94)00686-5}} {{pmid|7968212}}</ref> * Pindobind * Pindolol (presynaptic 5-HT1A) * Propranolol * Risperidone (weak) * Robalzotan * S-14063 <ref>Dabiré H, Bajjou R, Chaouche-Teyara K, Fournier B, De Nanteuil G, Laubie M, Safar M, Schmitt H. S14063: a new potent 5-HT1A receptor antagonist devoid of beta-adrenoceptor blocking properties. ''Eur J Pharmacol''. 1991 Oct 15;203(2):323-4. {{doi|10.1016/0014-2999(91)90735-9}} {{pmid|1686862}}</ref> * S-14489 (mixed 5-HT1A autoreceptor agonist / postsynaptic 5-HT1A antagonist)<ref>Millan MJ, Canton H, Gobert A, Lejeune F, Rivet JM, Bervoets K, Brocco M, Widdowson P, Mennini T, Audinot V, et al. Novel benzodioxopiperazines acting as antagonists at postsynaptic 5-HT1A receptors and as agonists at 5-HT1A autoreceptors: a comparative pharmacological characterization with proposed 5-HT1A antagonists. ''J Pharmacol Exp Ther''. 1994 Jan;268(1):337-52. {{pmid|8301575}}</ref> * SB-272183 (mixed 5-HT1A/B/D antagonist)<ref>Kling A, Lange UE, Mack H, Bakker MH, Drescher KU, Hornberger W, Hutchins CW, Möller A, Müller R, Schmidt M, Unger L, Wicke K, Schellhaas K, Steiner G. Synthesis and SAR of highly potent dual 5-HT1A and 5-HT1B antagonists as potential antidepressant drugs. ''Bioorg Med Chem Lett''. 2005 Dec 15;15(24):5567-73. {{doi|10.1016/j.bmcl.2005.04.077}} {{pmid|16219465}}</ref> * SB-649,915 * SDZ-216-525 * SL88.0338 <ref>Griebel G, Rodgers RJ, Perrault G, Sanger DJ. Behavioural profiles in the mouse defence test battery suggest anxiolytic potential of 5-HT(1A) receptor antagonists. ''Psychopharmacology (Berl)''. 1999 May;144(2):121-30. {{doi|10.1007/s002130050984}} {{pmid|10394992}}</ref> * Spiperone * Spiramide * Spiroxatrine * UH-301 * WAY-100,135 * WAY-100,635 * Wf-516 <ref>Saijo T, Maeda J, Okauchi T, Maeda J, Morio Y, Kuwahara Y, Suzuki M, Goto N, Fukumura T, Suhara T, Higuchi M. Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain. PLoS One. 2012;7(8):e42589. {{doi|10.1371/journal.pone.0042589|doi-access=free}} {{pmid|22880045}}</ref> * Xylamidine {{Div col end}}

===Allosteric modulators===

* Cholesterol – endogenous PAM<ref name="pmid19781522">{{cite journal |vauthors=Prasad R, Paila YD, Chattopadhyay A |title=Membrane cholesterol depletion enhances ligand binding function of human serotonin1A receptors in neuronal cells |journal=Biochem Biophys Res Commun |volume=390 |issue=1 |pages=93–6 |date=December 2009 |pmid=19781522 |doi=10.1016/j.bbrc.2009.09.072 |url=}}</ref> * Oleamide – endogenous PAM<ref name="pmid9391162">{{cite journal |vauthors=Thomas EA, Carson MJ, Neal MJ, Sutcliffe JG |title=Unique allosteric regulation of 5-hydroxytryptamine receptor-mediated signal transduction by oleamide |journal=Proc Natl Acad Sci U S A |volume=94 |issue=25 |pages=14115–9 |date=1997 |pmid=9391162 |pmc=28442 |doi=10.1073/pnas.94.25.14115 |url=|doi-access=free |bibcode=1997PNAS...9414115T }}</ref> * Zn2+ – endogenous NAM<ref name="pmid28455702">{{cite journal |vauthors=Satała G, Duszyńska B, Lenda T, Nowak G, Bojarski AJ |title=Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions |journal=Mol Neurobiol |volume=55 |issue=4 |pages=2897–2910 |date=2018 |pmid=28455702 |pmc=5842505 |doi=10.1007/s12035-017-0536-0 |url=}}</ref> * AM-2201 – exogenous PAM<ref name="pmid32324370">{{cite journal |vauthors=Yano H, Adhikari P, Naing S, Hoffman AF, Baumann MH, Lupica CR, Shi L |title=Positive Allosteric Modulation of the 5-HT1A Receptor by Indole-Based Synthetic Cannabinoids Abused by Humans |journal=ACS Chem Neurosci |volume=11 |issue=10 |pages=1400–1405 |date=2020 |pmid=32324370 |pmc=8275447 |doi=10.1021/acschemneuro.0c00034 |url=}}</ref>

== Genetics ==

The 5-HT1A receptor is coded by the ''HTR1A'' gene. There are several human polymorphisms associated with this gene. A 2007 review listed 27 single nucleotide polymorphisms (SNP).<ref name="pmid18047755">{{cite journal | vauthors = Drago A, Ronchi DD, Serretti A | title = 5-HT1A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies | journal = The International Journal of Neuropsychopharmacology | volume = 11 | issue = 5 | pages = 701–21 | date = August 2008 | pmid = 18047755 | doi = 10.1017/S1461145707008218 | doi-access = free }}</ref> The most investigated SNPs are C-1019G (rs6295), C-1018G,<ref name="pmid10412191">{{cite journal | vauthors = Wu S, Comings DE | title = A common C-1018G polymorphism in the human 5-HT1A receptor gene | journal = Psychiatric Genetics | volume = 9 | issue = 2 | pages = 105–6 | date = June 1999 | pmid = 10412191 | doi = 10.1097/00041444-199906000-00010 }}</ref> Ile28Val (rs1799921), Arg219Leu (rs1800044), and Gly22Ser (rs1799920).<ref name="pmid18047755"/> Some of the other SNPs are Pro16Leu, Gly272Asp, and the synonymous polymorphism G294A (rs6294). These gene variants have been studied in relation to psychiatric disorders with no definitive results.<ref name="pmid18047755"/>

== Protein-protein interactions ==

The 5-HT1A receptor has been shown to interact with brain-derived neurotrophic factor (BDNF), which may play a major role in its regulation of mood and anxiety.<ref name="pmid17401528">{{cite journal | vauthors = Anttila S, Huuhka K, Huuhka M, Rontu R, Hurme M, Leinonen E, Lehtimäki T | title = Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression | journal = Journal of Neural Transmission | volume = 114 | issue = 8 | pages = 1065–8 | year = 2007 | pmid = 17401528 | doi = 10.1007/s00702-007-0705-9 | s2cid = 19373406 }}</ref><ref name="pmid17559709">{{cite journal | vauthors = Guiard BP, David DJ, Deltheil T, Chenu F, Le Maître E, Renoir T, Leroux-Nicollet I, Sokoloff P, Lanfumey L, Hamon M, Andrews AM, Hen R, Gardier AM | display-authors = 6 | title = Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype | journal = The International Journal of Neuropsychopharmacology | volume = 11 | issue = 1 | pages = 79–92 | date = February 2008 | pmid = 17559709 | doi = 10.1017/S1461145707007857 | doi-access = free }}</ref>

=== Receptor oligomers ===

The 5-HT1A receptor forms heterodimers with the following receptors: 5-HT7,<ref>{{cite journal | vauthors = Renner U, Zeug A, Woehler A, Niebert M, Dityatev A, Dityateva G, Gorinski N, Guseva D, Abdel-Galil D, Fröhlich M, Döring F, Wischmeyer E, Richter DW, Neher E, Ponimaskin EG | display-authors = 6 | title = Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking | journal = Journal of Cell Science | volume = 125 | issue = Pt 10 | pages = 2486–99 | date = May 2012 | pmid = 22357950 | doi = 10.1242/jcs.101337 | hdl = 11858/00-001M-0000-000F-A828-A | url = http://pubman.mpdl.mpg.de/pubman/item/escidoc:1481617/component/escidoc:1481618/1481617.pdf | s2cid = 970339 | doi-access = free }}</ref> 5-HT1B, 5-HT1D, GABAB2, LPA1 (GPCR26), LPA3, S1P1, S1P3.<ref name=pmid11854302>{{cite journal | vauthors = Salim K, Fenton T, Bacha J, Urien-Rodriguez H, Bonnert T, Skynner HA, Watts E, Kerby J, Heald A, Beer M, McAllister G, Guest PC | display-authors = 6 | title = Oligomerization of G-protein-coupled receptors shown by selective co-immunoprecipitation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 18 | pages = 15482–5 | date = May 2002 | pmid = 11854302 | doi = 10.1074/jbc.M201539200 | doi-access = free }}</ref>

== See also == * 5-HT receptor * 5-HT1 receptor

== References == {{Reflist|35em}}

== External links == {{Commons category}} * {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2310 | title = 5-HT1A | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2008-11-24 | archive-date = 2012-09-02 | archive-url = https://web.archive.org/web/20120902024830/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2310 | url-status = dead }} *{{UCSC gene info|HTR1A}}

{{DEFAULTSORT:5-Ht1a Receptor}} Category:Serotonin receptors