Fig. 8: In vitro and in vivo effects of β-arrestin-biased 5-HT2A agonists.
From: Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential
A Scheme of NanoBit Internalization Assay for 5-HT2AR measuring loss of surface expression with the membrane impermeable LgBit. B 5-HT2AR internalization concentration response calculated as percent basal surface expression and normalized to 0% of max 5-HT response. Data represent mean and SEM from 3 independent experiments with 5-HT (black), DOI (blue), pimavanserin (grey), 25N-NBOMe (4) (green), 25N-N1-Nap (16) (red) and 25N-NBPh (17) (purple). C Cartoon showing the procedures used to induce tolerance in the head-twitch response (HTR) assay. Mice were injected with vehicle or drug once daily for 5 consecutive days and then challenged with (±)-DOI (1 mg/kg IP) 24 hours after the last injection. D Repeated administration of (±)-DOI and 25N-N1-Nap (16) (F2,16 = 16.68, p = 0.0001), but not pimavanserin (t10 = 1.067, 2-tailed p = 0.3111), induces a tolerance to the HTR induced by DOI. Mice was treated with vehicle, 25N-N1-Nap (16) (20 mg/kg/day SC), or (±)-DOI (10 mg/kg/day SC). Additional mice were treated with vehicle or pimavanserin (1 mg/kg/day SC). HTR counts are expressed as a percentage of the response in the respective control group; data from individual male C57BL/6 J mice as well as group means are shown. P-values are provided if there were significant differences between groups (Tukey’s test). E Pimavanserin blocks the response to (±)-DOI injected 20-minutes later (F3,16 = 8.19, p = 0.0016). HTR counts from individual mice as well as group means are shown. P values are provided if there were significant differences between groups (Tukey’s test). F 25N-N1-Nap (16) attenuates phencyclidine (PCP)-induced hyperactivity (pretreatment × PCP: F1,20 = 7.09, p = 0.015; pretreatment × PCP × time: F2,40 = 11.03, p = 0.0002). Locomotor activity was measured as distance traveled (cm), presented as group means ± SEM. N = 6 male C57BL/6 J mice/group. *p < 0.05, significant difference vs. vehicle; #p < 0.05, significant difference vs. PCP alone (Tukey’s test). G M100907 attenuates PCP-induced hyperactivity (pretreatment × PCP: F1,20 = 7.41, p = 0.0131). N = 6 male C57BL/6 J mice/group. *p < 0.05, significant difference vs. vehicle; #p < 0.05, significant difference vs. PCP alone (Tukey’s test). Drug doses are presented as mg/kg. Source data are provided as a Source Data file.
