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5-HT system

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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]


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)

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.


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. Rev108 (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 9780071481274Similarly, 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.

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