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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| 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 | 5-hydroxytryptophan 5-HT Receptor Serotonin antagonists Pharmacology |
| Citations | 60 |
| Key findings | 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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
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- Effect of psilocybin on marble burying in ICR mice: role of 5-HT1A receptors and implications for the treatment of obsessive-compulsive disorder. Translational Psychiatry May 10, 2023
- Are “mystical experiences” essential for antidepressant actions of ketamine and the classic psychedelics? European Archives of Psychiatry and Clinical Neuroscience February 27, 2024
- Rapid antidepressant-like effect of non-hallucinogenic psychedelic analog lisuride, but not hallucinogenic psychedelic DOI, in lipopolysaccharide-treated mice Pharmacology, Biochemistry, and Behavior December 5, 2022
- Effect of chemically synthesized psilocybin and psychedelic mushroom extract on molecular and metabolic profiles in mouse brain. Molecular Psychiatry July 1, 2024
- A Comprehensive Review of the Current Status of the Cellular Neurobiology of Psychedelics Biology October 28, 2023
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Cites 47
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine June 1, 2021
- The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology April 26, 2017
- Amphetamine, 3,4-Methylenedioxymethamphetamine, Lysergic Acid Diethylamide, and Metabolites of the Catecholamine Neurotransmitters Are Agonists of a Rat Trace Amine Receptor Molecular Pharmacology December 1, 2001
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