Serotonin, But Not N -Methyltryptamines, Activates the Serotonin 2A Receptor Via a β-Arrestin2/Src/Akt Signaling Complex In Vivo
Cullen L. Schmid, Laura M Bohn
Journal of Neuroscience October 6, 2010 DOI: 10.1523/jneurosci.1665-10.2010 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Wild-type and β-arrestin2 knockout mice |
| Interventions | Serotonin 5-hydroxy-L-tryptophan N-methyltryptamines |
| Topics | Serotonin |
| Keywords | Neurotransmitter Agonist Protein kinase b 5-HT Receptor Endocrinology Pharmacology Signal transduction |
| Citations | 172 |
| Key findings | Serotonin engages a β-arrestin2-mediated signaling cascade at 5-HT2A receptors in the frontal cortex, while N-methyltryptamines do not, revealing agonist-directed signaling in vivo. |
Abstract
Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT 2A R). Although serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT 2A R and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactive N -methyltryptamines by its ability to engage a β-arrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy- l -tryptophan (5-HTP) induce a head-twitch response in wild-type (WT) mice that is a behavioral proxy for 5-HT 2A R activation. The response in β-arrestin2 knock-out (βarr2-KO) mice is greatly attenuated until the doses are elevated, at which point, βarr2-KO mice display a head-twitch response that can exceed that of WT mice. Direct administration of N -methyltryptamines also produces a greater response in βarr2-KO mice. Moreover, the inhibition of N -methyltransferase blocks 5-HTP-induced head twitches in βarr2-KO mice, indicating that N -methyltryptamines, rather than serotonin, primarily mediate this response. Biochemical studies demonstrate that serotonin stimulates Akt phosphorylation in the frontal cortex and in primary cortical neurons through the activation of a β-arrestin2/phosphoinositide 3-kinase/Src/Akt cascade, whereas N -methyltryptamines do not. Furthermore, disruption of any of the components of this cascade prevents 5-HTP-induced, but not N -methyltryptamine-induced, head twitches. We propose that there is a bifurcation of 5-HT 2A R signaling that is neurotransmitter and β-arrestin2 dependent. This demonstration of agonist-directed 5-HT 2A R signaling in vivo may significantly impact drug discovery efforts for the treatment of disorders wherein hallucinations are part of the etiology, such as schizophrenia, or manifest as side effects of treatment, such as depression.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 71
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Structure-based discovery of nonhallucinogenic psychedelic analogs Science January 27, 2022
- Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways Current Topics in Behavioral Neurosciences 2017
- Psychedelic-inspired drug discovery using an engineered biosensor. Cell April 28, 2021
- The promises and perils of psychedelic pharmacology for psychiatry. Nature Reviews Drug Discovery June 1, 2022
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Cites 11
- Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex Journal of Neuroscience October 1, 2003
- Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines Journal of Medicinal Chemistry October 19, 2000
- PSD-95 Is Essential for Hallucinogen and Atypical Antipsychotic Drug Actions at Serotonin Receptors Journal of Neuroscience June 3, 2009
- The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen Psychopharmacology February 19, 2010
- Bufotenine: toward an understanding of possible psychoactive mechanisms. Journal of Psychoactive Drugs 2000
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