Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 receptors in the head twitch response induced by 5-hydroxytryptophan and psilocybin: Translational implications

Abstract

AbstractThere is increasing interest in the therapeutic potential of psilocybin in psychiatric disorders. In common with other serotonergic psychedelics, psilocybin is thought to act via the 5-HT2A receptor (5-HT2AR). Serotonin is the endogenous ligand of 5-HTR. In rodents, the serotonin precursor, 5-hydroxytryptophan (5-HTP), and psilocybin, induce a characteristic head twitch response (HTR), which is correlated with the human psychedelic trip in intensity and duration. We examined the role of other serotonergic receptors and the trace amine associated receptor 1 (TAAR1) in modulating HTR induced by 5-HTP and psilocybin. Male C57BL/6J mice (11 weeks old, ~30g) were administered 5-HTP, 50-250 mg/kg intraperitoneally (i.p.) or 200 mg/kg i.p. after pretreatment with 5-HT/TAAR1 receptor modulators. Psilocybin was administered at 0.1-51.2 mg/kg i.p. or at 4.4 mg/kg i.p. preceded by 5-HT/TAAR1 receptor modulators. HTR was assessed in a custom-built magnetometer. 5-HTP and psilocybin induced a dose dependent increase in the frequency of HTR over 20 minutes with attenuation by the 5-HT2AR antagonist, M100907 (volanserin), and the 5-HT1AR agonist, 8-OH-DPAT. The 5-HT2CR antagonist, RS102221, enhanced HTR at lower doses but reduced it at higher doses for 5-HTP and psilocybin. The TAAR1 antagonist, EPPTB, reduced 5-HTP-but not psilocybin-induced HTR. We have confirmed the key role of 5-HT2AR in HTR and have demonstrated an effect of 5-HT1AR and a bimodal contribution of 5-HT2CR as well as a role of TAAR1 in modulating HTR induced by 5-HTP. Compounds that modulate HTR induced by psychedelics have a potentially important role in the emerging therapeutic use of these compounds.Significance StatementWe have confirmed the key role of 5-HT2AR in in the induction of HTR by 5-HTP and psilocybin, have demonstrated the effect of a 5-HT1AR agonist to attenuate HTR and a bimodal contribution of 5-HT2CR as well as a role of TAAR1 in modulating HTR induced by 5-HTP. Compounds that modulate HTR induced by psychedelics have a potentially important role in the emerging therapeutic use of these compounds.Visual Abstract