Head-twitch response explained

The head-twitch response (HTR) is a rapid side-to-side head movement that occurs in mice and rats after the serotonin 5-HT2A receptor is activated.^[1] The prefrontal cortex may be the neuroanatomical locus mediating the HTR.^[2] Many serotonergic hallucinogens, including lysergic acid diethylamide (LSD), induce the head-twitch response, and so the HTR is used as a behavioral model of hallucinogen effects. However while there is generally a good correlation between compounds that induce head twitch in mice and compounds that are hallucinogenic in humans,^[3] it is unclear whether the head twitch response is primarily caused by 5-HT2A receptors, 5-HT2C receptors or both, though recent evidence shows that the HTR is mediated by the 5-HT2A receptor and modulated by the 5-HT2C receptor.^{[4] [5]} Also, the effect can be non-specific, with head twitch responses also produced by some drugs that do not act through 5-HT₂ receptors, such as phencyclidine, yohimbine, atropine and cannabinoid receptor antagonists. As well, compounds such as 5-HTP, fenfluramine, 1-Methylpsilocin, Ergometrine, and 3,4-di-methoxyphenethylamine (DMPEA) can also produce head twitch and do stimulate serotonin receptors, but are not hallucinogenic in humans.^{[6] [7]} This means that while the head twitch response can be a useful indicator as to whether a compound is likely to display hallucinogenic activity in humans, the induction of a head twitch response does not necessarily mean that a compound will be hallucinogenic, and caution should be exercised when interpreting such results.^[8]

Notes and References

1. Nakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, Oka R, Hiraga H, Tadano T . 6 . Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives . Neurotoxicology . 25 . 1–2 . 223–32 . January 2004 . 14697897 . 10.1016/S0161-813X(03)00101-3 . 2004NeuTx..25..223N .
2. Willins DL, Meltzer HY . Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats . The Journal of Pharmacology and Experimental Therapeutics . 282 . 2 . 699–706 . August 1997 . 9262333 .
3. Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD . Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species . Neuropharmacology . 167 . 107933 . May 2020 . 31917152 . 10.1016/j.neuropharm.2019.107933 . 9191653 .
4. Sakaue M, Ago Y, Sowa C, Sakamoto Y, Nishihara B, Koyama Y, Baba A, Matsuda T . 6 . Modulation by 5-hT2A receptors of aggressive behavior in isolated mice . Japanese Journal of Pharmacology . 89 . 1 . 89–92 . May 2002 . 12083749 . 10.1254/jjp.89.89 . free .
5. Carbonaro TM, Eshleman AJ, Forster MJ, Cheng K, Rice KC, Gatch MB . The role of 5-HT2A, 5-HT 2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice . Psychopharmacology . 232 . 1 . 275–84 . January 2015 . 24985890 . 4282596 . 10.1007/s00213-014-3658-3 .
6. Corne . S. J. . Pickering . R. W. . 1967 . A possible correlation between drug-induced hallucinations in man and a behavioural response in mice . Psychopharmacologia . en . 11 . 1 . 65–78 . 10.1007/BF00401509 . 5302272 . 3148623 . 0033-3158.
7. Book: Shulgin . Alexander . PiHKAL: A Chemical Love Story . Shulgin . Ann . Transform Press . 1991 . 978-0-9630096-0-9 . 1st . 614–616 . en.
8. Canal CE, Morgan D . Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model . Drug Testing and Analysis . 4 . 7–8 . 556–76 . July 2012 . 22517680 . 3722587 . 10.1002/dta.1333 .