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| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| Head-twitch response | 2/5 | https://en.wikipedia.org/wiki/Head-twitch_response | reference | science, encyclopedia | 2026-05-05T07:29:09.145592+00:00 | kb-cron |
== Procedure == The HTR method is reliable, straightforward, and simple to perform in that it merely involves direct behavioral observation following drug administration. No animal training or expensive equipment are necessarily required. The HTR can be measured in a single animal or a group of animals and can be observed in real-time or via video-recording and later observation. It can also be recorded via a magnet attached to the head or ear. DOI is the most commonly used psychedelic to induce the HTR. DOI and other psychedelics show a biphasic or inverted U-shaped dose–response curve in terms of HTR induction. For example, no HTR is observed at 0.1 mg/kg DOI, maximal HTR is observed at 1 to 10 mg/kg, and lesser HTR is observed at 3 to 20 mg/kg in rodents. The doses can vary depending on the rodent species and strain. Hence, based on the preceding, proper drug dosing is important for induction of the HTR. A drawback of the HTR assay is that manual observation can be very laborious and time-consuming. More recently however, semi- and fully-automated forms of the assay, notably allowing for the possibility of high-throughput screening, have been developed.
== Mechanisms ==
The HTR produced by serotonergic psychedelics, which act as non-selective serotonin receptor agonists, appears to be mediated specifically by agonism of the serotonin 5-HT2A receptor. Selective and non-selective serotonin 5-HT2A antagonists, like volinanserin (M100907), can block production of the HTR by serotonergic psychedelics. Similarly, the HTR of psychedelics is absent in serotonin 5-HT2A receptor knockout mice. Restoration of the serotonin 5-HT2A receptor to cortical neurons in these knockout mice can restore the HTR. The intracellular signaling cascade activated by the serotonin 5-HT2A receptor to produce the HTR appears to be the Gq pathway. Relatedly, there are robust correlations between serotonin 5-HT2A receptor Gq efficacy and magnitude of the HTR among psychedelic drugs. However, the responsible cascades have not been definitively elucidated, and other pathways, such as the Gs and β-arrestin2 pathways, have also been implicated in other studies. The HTR is mediated by central serotonin 5-HT2A receptor activation. Hence, if a given serotonin 5-HT2A receptor agonist produces the HTR, this can be considered evidence that the drug is able to cross the blood–brain barrier and exert central effects. 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. However, other brain areas have also been independently implicated. For example, local injection of serotonergic psychedelics into the claustrum produces wet dog shakes (i.e., the HTR) in rats as well. 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. The HTR is said to resemble a strong pinna reflex involving the whole head. The pinna reflex can be elicited by tactile stimulation, for example stimulation of the ear by a fine hair. In the case of the HTR however, the reflex occurs without tactile stimulation. 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). 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. The reasons for the biphasic or inverted U-shaped dose–response curve with psychedelics are unknown. However, activation of serotonin 5-HT2C and 5-HT1A receptors at higher doses appears to at least partly be involved. In contrast to the HTR, frontal cortex inositol monophosphate (IP1) turnover due to serotonin 5-HT2A receptor activation, which is associated with the hallucinogenic effects of serotonergic psychedelics, has an asymptotic dose–response curve akin to a saturation curve. Based on these findings, it was suggested that psychedelics may continue to increase serotonin 5-HT2A receptor activation at higher doses but that behavioral disruption limits the expression of the HTR. Tolerance and tachyphylaxis to the HTR and/or other effects of serotonergic psychedelics may be mediated by serotonin 5-HT2A receptor downregulation. LSD, psilocin, DOM, DOI, and DOB have all been found to reduce the density of brain serotonin 5-HT2A receptors in animals in vivo and/or to desensitize the receptor in transfected cell lines, and this downregulation has been found to recover very slowly. LSD has also been specifically shown to reduce brain serotonin 5-HT2A receptor signaling in animals. Conversely however, DMT, which is not associated with tolerance development in humans, did not desensitize the serotonin 5-HT2A receptor in cell lines. Activation of the serotonin 5-HT2A receptor β-arrestin2 pathway may mediate serotonin 5-HT2A receptor internalization and tolerance. However, findings are conflicting, as β-arrestin2 knockout mice still showed tolerance to the HTR induced by DOI. It is also notable that, in contrast to most G protein-coupled receptors (GPCRs), serotonin 5-HT2A receptor downregulation has been found to occur in response to both agonists and antagonists of the receptor. Besides serotonin 5-HT2A receptor downregulation, tolerance to psychedelics may also develop due to adaptations in downstream glutamate receptors. An alternative possibility to serotonin 5-HT2A receptor biased agonism is that the lack of tolerance with drugs like DMT may simply be due to their very short durations.