[1][3] Because of this, the HTR is widely employed in scientific research as an animal behavioral model of hallucinogen effects and in the discovery of new psychedelic drugs.

[1][3] The only other behavioral paradigms for assessment of psychedelic-like effects in animals at present are drug discrimination (DD) and, to a lesser extent, prepulse inhibition (PPI) and time perception.

[6] The HTR is a rapid, rhythmic side-to-side or rotational head movement that intermittently occurs in mice and rats in association with serotonin 5-HT2A receptor activation.

[6][9] Within a 10-minute period, between 4 to 68 head twitches have been observed following administration of DOI depending on the dose, enantiomer, and rodent species and strain.

[10] Serotonin 5-HT2A receptor agonists show an inverted U-shaped dose–response curve for induction of the HTR in terms of its frequency.

[7] HTR-like behaviors are also induced by psychedelics in other animal species, for instance cats and stump-tailed macaque monkeys.

[7] The HTR method is reliable and simple to perform in that it simply involves direct behavioral observation following drug administration.

[8] More recently however, semi- and fully-automated forms of the assay, notably allowing for the possibility of high-throughput screening, have been developed.

[36][6] Activation of serotonin 5-HT2A receptors in the medial prefrontal cortex (mPFC), with layer V pyramidal neurons especially implicated and with subsequent release of glutamate in this area, may be the origin of the HTR.

[1][9] Serotonin 5-HT2A and metabotropic glutamate mGlu2 receptor heterodimeric complexes may or may not be important for induction of the HTR by psychedelics, with research findings in this area being conflicting.

[6] The HTR induced by the serotonin precursor 5-hydroxytryptophan (5-HTP) has been found to be sensitive to environmental interference by background noise and can be prevented by local anesthesia of the pinna (outer part of the ear).

[6][9][46] These findings suggest that the HTR might be due specifically to disturbances of auditory sensory processing, although more research is needed to confirm this possibility.

[8] Conversely however, DMT, which is not associated with tolerance development in humans, did not desensitize the serotonin 5-HT2A receptor in cell lines.

[7] Despite the preceding limitations, the assay has strong predictive validity for hallucinogenic effects of serotonin 5-HT2A receptor agonists in humans.

[17] The HTR can be non-specific and can have false positives, with head twitches also produced by some drugs that do not act through serotonin 5-HT2 receptors.

[6] A number of other drugs, including the acetylcholine receptor agonist carbachol, opioids, and thyrotropin-releasing hormone (TRH) among others, have also been reported to induce the HTR.

[64][1][5][6] The HTR is among the only animal behavioral tests that can reliably distinguish between hallucinogenic and non-hallucinogenic serotonin 5-HT2A receptor agonists.

[26][65] In any case, it is thought that partial agonism with sufficiently low efficacy for specific intracellular signaling pathways underlies the lack of HTR and psychedelic effects with non-hallucinogenic serotonin 5-HT2A receptor agonists.

[3][2] This is the case even with psychedelics that are not themselves monoamine oxidase (MAO) substrates, indicating that the potentiation is not simply due to inhibition of their metabolism.

[2] In contrast to MAOIs, serotonin reuptake inhibitors (SRIs), including citalopram, fluoxetine, fluvoxamine, and imipramine, do not affect the HTR induced by DOI.

[7] Unlike SRIs, chronic administration of serotonin–norepinephrine reuptake inhibitors (SNRIs) has been found to decrease the DOI-induced HTR.

[3] NMDA receptor antagonists like phencyclidine (PCP), ketamine, and dizocilpine (MK-801) have been found to enhance the DOI-induced HTR as well.

[27] Studies published in the 1960s and 1970s had shown that serotonin receptor antagonists, such as cinanserin, methysergide, and cyproheptadine, blocked the hallucinogen-like effects of psychedelics in animals.

[61][8][16][89] Richard Glennon and colleagues further supported mediation of the hallucinogen-like effects of psychedelics by serotonin 5-HT2 receptor agonism with subsequent studies, for instance employing drug discrimination, in 1983 and thereafter.

[8][26] de la Fuente Revenga and colleagues developed a fully automated HTR test based on Halberstadt's work and published their system in 2019.