Fig. 6. 5-HT2A-Gq signaling predicts psychedelic potential.
A–G Activity in the HTR assay can be predicted based on 5-HT2A receptor Gq-efficacy. As predicted, 25O-NBOMe (32) (F5,26 = 37.01, p < 0.0001), 2C2-NBOMe (31) (W6,12.67 = 96.28, p < 0.0001), and 25O-NBcP (33) (F5,25 = 20.57, p < 0.0001) induced head twitches, whereas 25O-NBPh-10’-OH (35) (F4,27 = 2.58, p = 0.0601), 25O-NB-3-I (34) (F5,25 = 0.26, p = 0.9288), and 25D-N1-Nap (26) (F3,20 = 0.37, p = 0.7748) did not induce head twitches. (H) Pretreatment with the Gαq/11 inhibitor YM-254890 blocks the HTR induced by R-(-)-DOI (F3,12 = 8.69, p = 0.0025). Mice were treated ICV with YM-254890 or vehicle and then all of the animals received R-(-)-DOI (1 mg/kg IP) 15 minutes later. (I) Pretreatment with the phospholipase C (PLC) inhibitor edelfosine blocks the HTR induced by R-(-)-DOI (F2,16 = 11.34, p = 0.0009) and 25N-NBOMe (4) (F2,16 = 6.40, p = 0.0091). Mice received three consecutive injections of vehicle or the indicated dose of edelfosine at 20-minute intervals and then a HTR-inducing drug was administered 10 minutes after the third injection. HTR counts from individual male C57BL/6 J mice as well as group means are shown. P values are provided if there were significant differences vs. vehicle control (Tukey’s test or Dunnett’s T3 test). The dose of YM-254890 is presented in µg; other drug doses are presented as mg/kg. Source data are provided as a Source Data file.