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Functional selectivity at the serotonin 2A receptor: differential signaling by serotonin and dimethylated tryptamines
Author(s) -
Schmid Cullen L,
Bohn Laura M
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.769.3
Subject(s) - tryptamines , tryptamine , serotonin , protein kinase b , 5 ht receptor , functional selectivity , chemistry , pharmacology , phosphorylation , agonist , neuroscience , receptor , biology , biochemistry
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.