Functional selectivity at the serotonin 2A receptor: differential signaling by serotonin and dimethylated tryptamines
Cullen L. Schmid, Laura M Bohn
The FASEB Journal April 1, 2010 DOI: 10.1096/fasebj.24.1_supplement.769.3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice (including βarrestin2 knockout mice) and primary cortical neuronal cultures |
| Intervention | Serotonin |
| Measures | Head twitch response, AKT phosphorylation |
| Topics | Serotonin |
| Key points | Serotonin induces 5-HT2AR-mediated AKT phosphorylation in the frontal cortex and primary neurons, and the head twitch response depends on βarrestin2 and AKT. In contrast, 5-MeO-DMT does not induce AKT phosphorylation and elicits the head twitch response independently of βarrestin2 and AKT, with enhanced responses in βarrestin2 knockout mice. |
Abstract
Serotonin and the hallucinogenic metabolites of tryptamines, dimethylated tryptamines, activate the serotonin 2A receptor (5‐HT2AR), which is implicated in numerous mental health disorders. We have previously demonstrated that the 5‐HT2AR is differentially regulated by βarrestin2 (βarr2) depending upon the agonist; here we utilized βarr2 knockout mice to compare signaling profiles in vivo, by assessing the head twitch response (which serves as a behavioral model for selective 5‐HT2AR activation), and in vitro, by assessing kinase activation. We demonstrate that serotonin leads to 5‐HT2AR‐mediated phosphorylation of the serine/threonine kinase AKT in the mouse frontal cortex and in primary neuronal cultures and that the head twitch response occurs in a βarr2 and AKT dependent manner. In contrast, a metabolism‐resistant dimethylated tryptamine, 5‐MeO‐DMT, does not induce phosphorylation of AKT in frontal cortex or in cortical neurons and induces the head twitch response regardless of βarr2 or inhibition of AKT expression. We also show that in the absence of βarr2, the head twitch response is enhanced in response to 5‐MeO‐DMT, suggesting that while βarr2 mediates serotonin signaling at the 5‐HT2AR, it dampens dimethylated tryptamine signaling at this receptor. Funding: R01 DA025158 , NIDA.
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| 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 |