5-HT Receptor System

5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems.[1][2][3] They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine / norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. The serotonin receptors influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. The serotonin receptors are the target of a variety of pharmaceutical and recreational drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens.[4]

5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors are found in the central and peripheral nervous systems.[1][2] They can be divided into 7 families of G protein-coupled receptors except for the 5-HT3 receptor, a ligand-gated ion channel, which activates an intracellular second messenger cascade to produce an excitatory or inhibitory response. In 2014, a novel 5-HT receptor was isolated from the small white butterfly, Pieris rapae, and named pr5-HT8. It does not occur in mammals and shares relatively low similarity to the known 5-HT receptor classes.

The 7 general serotonin receptor classes include a total of 14 known serotonin receptors.[6] The specific types have been characterized as follows:[7][8][9]

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Receptor	Blood Vessel	CNS	Potential	Function	Drugs that binds to this receptor
5-HT1A	Yes	Yes	Inhibitory	Addiction Aggression Anxiety Appetite Autoreceptor Blood Pressure Cardiovascular Function Emesis Heart Rate Impulsivity Memory Mood Nausea Nociception Penile Erection Pupil Dilation Respiration Sexual Behavior Sleep Sociability Thermoregulation Vasoconstriction	– Analgesics (agonists) – Antidepressants – Anxiolytics (antagonist)
5-HT1B	Yes	Yes	Inhibitory	Addiction Aggression Anxiety Autoreceptor Learning Locomotion Memory Mood Penile Erection Sexual Behavior Vasoconstriction	– Migraines (e.g. triptans)
5-HT1D	Yes	Yes	Inhibitory	Anxiety Autoreceptor Locomotion Vasoconstriction	– Migraines (e.g. triptans)
5-HT1E	Yes	Yes	Inhibitory	Unknown	Unknown
5-HT1F	No	Yes	Inhibitory	Migrain	Unknown
5-HT2A			Excitatory	Addiction (potentially modulating) Anxiety Appetite Cognition Imagination Learning Memory Mood Perception Sexual Behavior Sleep Thermoregulation Vasoconstriction	– Atypical antipsychotics (antagonist) – Psychedelics (agonists) 25I-NBOMe (Full agonist) 5-MeO-DMT BZP Bufotenin DMT DOM Ergonovine Lisuride LSD Mescaline Myristicin PNU-22394 (Partial agonist) Psilocin Psilocybin TFMPP (partial agonist or antagonist) – NaSSAs – Treating serotonin syndrome (antagonists; e.g. cyproheptadine) – Sleeping aid (antagonists; e.g. trazodone)
5-HT2B	Yes	Yes	Excitatory	Anxiety Appetite Cardiovascular Function GI Motility Sleep Vasoconstriction	Migraines (antagonists)

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Receptor	Blood Vessel	CNS	Potential	Function	Drugs that binds to this receptor
5-HT2C	Yes	Yes	Excitatory	Addiction. (potentially modulating) Anxiety Appetite GI Motility Heteroreceptor for norepinephrine and dopamine Locomotion Mood Penile Erection Sexual Behavior Sleep Thermoregulation Vasoconstriction	Antidepressant (antagonists; e.g. agomelatine, fluoxetine, mirtazapine) Orexigenic (e.g. mirtazapine, clozapine and olanzapine; antagonists) Anorectic (Lorcaserin; agonist) Antipsychotic (Vabicaserin; agonists)
5-HT3	No	Yes	Excitatory	Addiction Anxiety Emesis GI Motility Learning Memory Nausea	Antiemetic Antidepressant (e.g. mirtazpine) antipsychotic (e.g. olanzapine, quetiapine)
5-HT4	No	Yes	Excitatory	Anxiety Appetite GI Motility Learning Memory Mood Respiration	Gastroprokinetics (e.g. Tegaserod)
5-HT5A	No	Yes	Inhibitory	Autoreceptor Locomotion Sleep	Unknown
5-HT5B	No	No	Inhibitory	Unknown	Unknown
5-HT6	No	Yes	Excitatory	Anxiety Cognition Learning Memory Mood	Antidepressant (antagonists and agonists) Anxiolytic (antagonists and agonist) Nootropic (antagonists) Anorectic (antagonists)
5-HT2C	Yes	Yes	Excitatory	Anxiety Autoreceptor Memory Mood Respiration Sleep Thermoregulation Vasoconstriction	Antidepressant (antagonists) Anxiolytics (antagonists) Nootropic (antagonists)

 

Full agonists

A serotonin full agonist is a chemical that binds to and activates a serotonin receptor and triggers a response, displaying full efficacy at that receptor.

Partial agonists

A serotonin partial agonist is a drug that binds to and activates a serotonin receptor, but only has partial efficacy at the receptor relative to a full agonist. Most classical psychedelic drugs are partial agonists of the 5-HT2A receptor; among them are LSD, psilocin and mescaline. Many antidepressants, anxiolytics/anti-anxiety drugs, and cluster headache medicines are partial serotonin receptor agonists.

Inverse agonists

A serotonin inverse agonist activates a serotonin receptor but has the opposite pharmacological effect. Inverse agonists trigger a specific response from a receptor, whereas antagonists inhibit the activity of the receptor. Some antipsychotics such as pimavanserin are 5-HT2A inverse agonists. 5-HT2A inverse agonists have been researched for the treatment of insomnia with limited success.

Releasing agents

A serotonin releasing agent is a drug that induces the release of serotonin from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of serotonin. Many recreational drugs are serotonin releasing agents; among them are MDMA, MDA and mephedrone. Many analgesics/pain-relievers and appetite suppressants are also serotonin releasing agents.

Reuptake inhibitor

A serotonin reuptake inhibitor inhibits the reabsorption of serotonin into the pre-synaptic neuron. Serotonin reuptake inhibitors do this by inhibiting the serotonin transporter, or SERT protein. Many antidepressants such as venlafaxine (Effexor), citalopram (Celexa) and amitriptyline are serotonin reuptake inhibitors. Many recreational drugs like cocaine and tramadol are also serotonin reuptake inhibitors.

Antagonists

A serotonin receptor antagonist is a type of receptor drug that inhibits action at serotonin receptors. Many antipsychotics like haloperidol or quetiapine and anti-emetics are serotonin receptor antagonists. One example is galanolactone, a chemical found in ginger, that acts as an anti-emetic via its action as a 5-HT3 antagonist.

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Reference:

[1]. Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP (1994). “International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin)”. Pharmacol. Rev. 46 (2): 157–203. PMID 7938165.

[2]. Frazer A, Hensler JG (1999). “Chapter 13: Serotonin Receptors”. In Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD (eds.). Basic Neurochemistry: MolecularCellular, and Medical Aspects. Philadelphia: Lippincott-Raven. pp. 263–292. ISBN 978-0-397-51820-3.

[3]. Beliveau, Vincent; Ganz, Melanie; Feng, Ling; Ozenne, Brice; Højgaard, Liselotte; Fisher, Patrick M.; Svarer, Claus; Greve, Douglas N.; Knudsen, Gitte M. (2017-01-04). “A High-Resolution In Vivo Atlas of the Human Brain’s Serotonin System”. Journal of Neuroscience. 37 (1): 120–128. doi:10.1523/jneurosci.2830-16.2016. PMC 5214625. PMID 28053035.

[4]. Nichols DE, Nichols CD (May 2008). “Serotonin receptors”. Chem. Rev. 108 (5): 1614–41. doi:10.1021/cr078224o.

[5]. Psychonaut wiki, Sertonergic Drugs. Accessed May 2020.

[6].Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 4. ISBN 9780071481274. Similarly, little is known about which of serotonin’s 14 known receptors must be activated to achieve an antidepressant response.

[7].Glennon RA, Dukat M, Westkaemper RB (2000-01-01). “Serotonin Receptor Subtypes and Ligands”. American College of Neurophyscopharmacology. Archived from the original on 21 April 2008. Retrieved 2008-04-11.

[8].”5-Hydroxytryptamine Receptors”. IUPHAR Receptor Database. International Union of Basic and Clinical Pharmacology. Retrieved 2008-04-11.

[9].Wesolowska A (2002). “In the search for selective ligands of 5-HT5, 5-HT6 and 5-HT7 serotonin receptors”. Polish Journal of Pharmacology.