Serotonin, But Not N -Methyltryptamines, Activates the Serotonin 2A Receptor Via a β-Arrestin2/Src/Akt Signaling Complex In Vivo
Journal of Neuroscience October 6, 2010 Cullen L. Schmid, Laura M Bohn 172 citations
Hallucinogens like psilocybin activate serotonin 2A receptors (5-HT2AR) to produce psychoactive effects. Serotonin itself, the natural neurotransmitter, also activates these receptors but does not normally cause hallucinations. This study shows that serotonin triggers a specific signaling pathway involving β-arrestin2, phosphoinositide 3-kinase, Src, and Akt in the frontal cortex of mice, whereas N-methyltryptamines (hallucinogens) do not. In mice lacking β-arrestin2, serotonin-induced head-twitch responses (a behavioral proxy for receptor activation) were greatly reduced unless doses were elevated, and N-methyltryptamines produced stronger responses. Blocking N-methyltransferase prevented serotonin precursor-induced head twitches in knockout mice, suggesting N-methyltryptamines, not serotonin, mediate that response. This agonist-directed signaling bifurcation may inform drug development for conditions like schizophrenia or depression where hallucinations occur.