5-HT1B receptor

Tissue distribution and function

5-HT1B receptors are widely distributed throughout the central nervous system with the highest concentrations found in the frontal cortex, basal ganglia, striatum, and the hippocampus. The function of the 5-HT1B receptor differs depending upon its location. In the frontal cortex, it is believed to act as a terminal receptor inhibiting the release of dopamine. In the basal ganglia and the striatum, evidence suggests 5-HT signaling acts on an autoreceptor, inhibiting the release of serotonin and decreasing glutamatergic transmission by reducing miniature excitatory postsynaptic potential (mEPSP) frequency, respectively. In the hippocampus, a recent study has demonstrated that activation of postsynaptic 5-HT1B heteroreceptors produces a facilitation in excitatory synaptic transmission which is altered in depression. When the expression of 5-HT1B in human cortex was traced throughout life, significant changes during adolescence were observed, in a way that is strongly correlated with the expression of 5-HT1E.

Outside of the CNS, the 5-HT1B receptor is also expressed on the endothelium of blood vessels, particularly in the meninges. Activation of these receptors results in vasoconstriction. The high distribution of vasoconstrictive 5-HT1B and 5-HT1D receptors around the brain makes them a valuable drug target for the treatment of migraines.

Blocking 5-HT1B receptor signalling also increases the number of osteoblasts, bone mass, and the bone formation rate.

Knockout mice lacking the 5-HT1B gene have been reported to have a higher preference for alcohol, although later studies failed to replicate such abnormalities in alcohol consumption. These mice have also been reported to have a lower measure of anxiety (such as on the elevated plus maze test) and a higher measure of aggression.

Under basal conditions, knockout mice present with a "normal" phenotype and exhibit a sucrose preference (lack of sucrose preference is considered a measure of anhedonia). However, after undergoing chronic unpredictable stress treatment to induce a "depression-like" phenotype these animals do not benefit from administration of selective serotonin reuptake inhibitor (SSRIs).

Activation of the serotonin 5-HT1B receptor appears to mediate the prosocial effects of entactogens acting as serotonin releasing agents like MDMA in animals. In addition, serotonin 5-HT1B receptor activation appears to mediate the locomotor hyperactivity of these agents. The serotonin 5-HT1B receptor also appears to be required for the persisting antidepressant- and anxiolytic-like effects as well as acute hypolocomotion of the serotonergic psychedelic and non-selective serotonin receptor agonist psilocybin in animals.

Ligands

Agonists

• 2ZEDMA (also a 5-HT2A agonist)
• 5-Carboxamidotryptamine (5-CT)
• 5-MAPB
• 5-MAPBT
• 6-MAPB
• 6-MAPBT
• Almotriptan
• Anpirtoline (D-16949)
• Avitriptan
• Batoprazine
• BK-5-MAPB
• BK-5-MAPBT
• BK-6-MAPB
• CGS-12066 (CGS-12066A, CGS-12066B)
• CP-93,129
• CP-94,253
• CP-122,288 (mixed 5-HT1B/1D agonist)
• CP-135,807 (mixed 5-HT1B/1D agonist)
• Dihydroergotamine
• Donitriptan
• Eletriptan
• Eltoprazine (DU-28853)
• Emodin-8-glucoside
• Ergotamine
• Fluprazine
• Frovatriptan
• L-741604
• Lisuride
• mCPP
• MDMA
• Methylergometrine (methylergonovine)
• Methylone
• Methysergide
• Naratriptan
• Oxymetazoline
• Pergolide
• PGI-7043
• PZKKN-94 (also a 5-HT6 antagonist)
• Rizatriptan
• RU-24969 (mixed 5-HT1A/1B agonist)
• (S)-DCPT
• Serotonin
• Sumatriptan
• TFMPP
• Tryptamine psychedelics (e.g., 5-MeO-DMT, DPT, psilocin/psilocybin)
• Zolmitriptan

Partial agonists

• Asenapine
• AZ10419369
• Bromocriptine
• Metergoline
• Naphthylpiperazine
• Vortioxetine
• Ziprasidone

Antagonists and inverse agonists

• Alprenolol
• AOP-208 (LB-208)
• AR-A000002 (AZD-8129)
• Aripiprazole
• AZD-1134
• AZD-3783
• AZ12320927
• Carteolol
• Elzasonan
• F-14258
• GR-55562
• GR-127935
• Isamoltane (CGP-361A)
• LY-393558
• Metitepine (methiothepin)
• NAS-181 (MCOMM)
• Oxprenolol
• Penbutolol
• Propranolol
• Risperidone
• SB-216,641
• SB-224,289 (inverse agonist)
• SB-236,057 (inverse agonist)
• SB-245,570
• SB-616234
• SB-649,915
• Tertatolol
• Yohimbine

Negative allosteric modulators

• 5-HT-moduline

Unknown

• Dextromethorphan

Genetics

In humans the protein is coded by the gene HTR1B.

A genetic variant in the promoter region, A-161T, has been examined with respect to personality traits and showed no major effect.

References

References

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7. (Apr 2013). "Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression". Nature Neuroscience.
8. (Jul 2014). "Transitions in the transcriptome of the serotonergic and dopaminergic systems in the human brain during adolescence". European Neuropsychopharmacology.
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10. (Apr 2002). "Molecular, pharmacological and functional diversity of 5-HT receptors". Pharmacology Biochemistry and Behavior.
11. (2022). "Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated". Front Psychiatry.
12. (April 2024). "MDMA enhances empathy-like behaviors in mice via 5-HT release in the nucleus accumbens". Sci Adv.
13. (December 2019). "Distinct neural mechanisms for the prosocial and rewarding properties of MDMA". Sci Transl Med.
14. (October 2021). "Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD". Neuropsychopharmacology.
15. (1 January 2002). "Behavioral Psychopharmacology of MDMA and MDMA-Like Drugs: A Review of Human and Animal Studies". Informa UK Limited.
16. (May 1993). "Serotonin1B receptor activation mimics behavioral effects of presynaptic serotonin release". Neuropsychopharmacology.
17. (January 1999). "Locomotor response to MDMA is attenuated in knockout mice lacking the 5-HT1B receptor". Psychopharmacology.
18. (December 2024). "ACNP 63rd Annual Meeting: Poster Abstracts P609-P914: P691. The Non-Hallucinogenic Serotonin 1B Receptor is Necessary for the Persisting Behavioral Effects of Psilocybin in Mice". Neuropsychopharmacology.
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21. (July 2025). "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics". Neuron.
22. (February 2025). "Simultaneous 5-HT1BR agonist/5-HT6R antagonist action as a potential treatment of Parkinson's disease and its comorbidities". J Pharmacol Exp Ther.
23. (Mar 2003). "Behavioral pharmacology of AR-A000002, a novel, selective 5-hydroxytryptamine(1B) antagonist". The Journal of Pharmacology and Experimental Therapeutics.
24. (Sep 1998). "SB-224289--a novel selective (human) 5-HT1B receptor antagonist with negative intrinsic activity". British Journal of Pharmacology.
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27. (2003). "Allelic variants of the tryptophan hydroxylase (A218C) and serotonin 1B receptor (A-161T) and personality traits". Neuropsychobiology.