Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications
Orr Shahar, Alexander Botvinnik, Noam Esh-Zuntz, Michal Brownstien, Rachel Wolf, Amit Lotan, Gilly Wolf, Bernard Lerer, Tzuri Lifschytz
International Journal of Molecular Sciences November 16, 2022 DOI: 10.3390/ijms232214148 via OpenAlex
Summary
AI-generated from the abstractPsilocybin and the serotonin precursor 5-HTP produce a characteristic head twitch response in mice, which is linked to the human psychedelic experience. This response depends primarily on the 5-HT2A receptor, as blocking it with M100907 reduced twitching. Activating the 5-HT1A receptor with 8-OH-DPAT also suppressed the response, while blocking the 5-HT2C receptor with RS-102221 had a bimodal effect—enhancing twitching at lower doses but reducing it at higher doses. Blocking the trace amine-associated receptor 1 (TAAR1) with EPPTB reduced 5-HTP-induced twitching but not psilocybin-induced twitching. These findings highlight multiple receptor systems that could modulate psychedelic effects and may inform therapeutic applications.
Study at a glance
| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Population | Male C57BL/6J mice (11 weeks, ~30 g) |
| Interventions | 5-HTP psilocybin M100907 8-OH-DPAT RS-102221 EPPTB |
| Dose | 5-HTP 50-250 mg/kg i.p., 200 mg/kg i.p.; psilocybin 0.1-25.6 mg/kg i.p., 4.4 mg/kg i.p. |
| Duration | 20 minutes |
| Topics | Psilocybin Serotonin |
| Keywords | Neuroscience 5-hydroxytryptophan 5-HT Receptor Serotonin antagonists |
| Citations | 60 |
| Key finding | The head twitch response induced by psilocybin and 5-HTP is modulated by 5-HT2A, 5-HT1A, 5-HT2C, and TAAR1 receptors, with the 5-HT2A receptor playing a key role and TAAR1 selectively influencing 5-HTP-induced responses. |
Abstract
There is increasing interest in the therapeutic potential of psilocybin. In rodents, the serotonin precursor, 5-hydroxytryptophan (5-HTP) and psilocybin induce a characteristic 5-HT2A receptor (5-HT2AR)-mediated head twitch response (HTR), which is correlated with the human psychedelic trip. We examined the role of other serotonergic receptors and the trace amine -associated receptor 1 (TAAR1) in modulating 5-HTP- and psilocybin-induced HTR. Male C57BL/6J mice (11 weeks, ~30 g) were administered 5-HTP, 50–250 mg/kg i.p., 200 mg/kg i.p. after pretreatment with 5-HT/TAAR1 receptor modulators, psilocybin 0.1–25.6 mg/kg i.p. or 4.4 mg/kg i.p., immediately 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 min with attenuation by the 5-HT2AR antagonist, M100907, and the 5-HT1AR agonist, 8-OH-DPAT. The 5-HT2CR antagonist, RS-102221, enhanced HTR at lower doses but reduced it at higher doses. The TAAR1 antagonist, EPPTB, reduced 5-HTP- but not psilocybin-induced HTR. We have confirmed the key role of 5-HT2AR in HTR, an inhibitory effect of 5-HT1AR, a bimodal contribution of 5-HT2CR and a role of TAAR1 in modulating HTR induced by 5-HTP. Compounds that modulate psychedelic-induced HTR have important potential in the emerging therapeutic use of these compounds.