Gs signaling pathway distinguishes hallucinogenic and nonhallucinogenic 5-HT2AR agonists induced head twitch response in mice

Abstract

5- HT2A receptor is a member of the family A G-protein-coupled receptor. It is involved in many psychiatric disorders, such as depression, addiction and Parkinson's disease. 5-HT2AR targeted drugs play an important role in regulating cognition, memory, emotion and other physiological function by coupling G proteins, and their most notable function is stimulating the serotonergic hallucination. However, not all 5-HT2AR agonists exhibit hallucinogenic activity, such as lisuride. Molecular mechanisms of these different effects are not well illustrated. This study suggested that 5-HT2AR coupled both Gs and Gq protein under hallucinogenic agonists DOM and 25CN–NBOH stimulation, but nonhallucinogenic agonist lisuride and TBG only activates Gq signaling. Moreover, in head twitch response (HTR) model, we found that cAMP analogs 8-Bromo-cAMP and PDE4 inhibitor Rolipram could increase HTR, while Gs protein inhibitor Melittin could reduce HTR. Collectively, these results revealed that Gs signaling is a key signaling pathway that may distinguish hallucinogenic agonists and nonhallucinogenic agonists.