G signaling pathway distinguishes hallucinogenic and nonhallucinogenic 5-HTR agonists induced head twitch response in mice.

5- HT 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-HTR 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-HTR agonists exhibit hallucinogenic activity, such as lisuride. Molecular mechanisms of these different effects are not well illustrated. This study suggested that 5-HTR coupled both G and G protein under hallucinogenic agonists DOM and 25CN-NBOH stimulation, but nonhallucinogenic agonist lisuride and TBG only activates G signaling. Moreover, in head twitch response (HTR) model, we found that cAMP analogs 8-Bromo-cAMP and PDE4 inhibitor Rolipram could increase HTR, while G protein inhibitor Melittin could reduce HTR. Collectively, these results revealed that G signaling is a key signaling pathway that may distinguish hallucinogenic agonists and nonhallucinogenic agonists.