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

Abstract

5- HT_2A 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-HT_2AR 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-HT_2AR agonists exhibit hallucinogenic activity, such as lisuride. Molecular mechanisms of these different effects are not well illustrated. This study suggested that 5-HT_2AR coupled both G_s and G_q protein under hallucinogenic agonists DOM and 25CN-NBOH stimulation, but nonhallucinogenic agonist lisuride and TBG only activates G_q 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_s protein inhibitor Melittin could reduce HTR. Collectively, these results revealed that G_s signaling is a key signaling pathway that may distinguish hallucinogenic agonists and nonhallucinogenic agonists.

Keywords: 5-HT(2A)R; G(s)-protein; Hallucinogenic agonist; Head twitch response.