Head-twitch response

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A Wistar rat, one of the animal species in which serotonergic psychedelics induce head twitches. Wistar rat.jpg
A Wistar rat, one of the animal species in which serotonergic psychedelics induce head twitches.

The head-twitch response (HTR), also sometimes known as wet dog shakes (WDS) in rats, is a rapid side-to-side head movement that occurs in mice and rats when the serotonin 5-HT2A receptor is activated. [1] [2] Serotonergic psychedelics, including lysergic acid diethylamide (LSD), induce the HTR, and so the HTR is widely used as an animal behavioral model of hallucinogen effects and to discover new psychedelic drugs. [1] [3] HTR-like effects are also induced by psychedelics in other animal species, for instance cats and stump-tailed macaque monkeys. [1] Other related behaviors to head twitches induced by serotonergic agents include limb jerks and body scratches. [4] The only other behavioral paradigms for assessment of psychedelic-like effects in animals are drug discrimination (DD), prepulse inhibition (PPI), and time perception. [5] [6]

Contents

Mechanisms

Selective and non-selective serotonin 5-HT2A receptor antagonists, like volinanserin (M100907), can block the HTR of serotonergic psychedelics. [1] [6] [7] Similarly, the HTR of psychedelics is absent in serotonin 5-HT2A receptor knockout mice. [1] [6] [7] 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. [8] [1] [7] [9] However, other brain areas have also been independently implicated. [1]

Scientific validity

Head twitches do not occur with psychedelics in humans [5] and head twitches lack face validity as an animal behavioral proxy of psychedelic effects. [6] In any case, it has been said that head twitches might resemble sensory disturbances during hallucinogenic experiences. [3] Despite the preceding limitations, the assay has strong predictive validity. [6] There is a good correlation between the capacity of serotonergic psychedelics to induce head twitches in rodents and their reported potency in inducing hallucinogenic effects in humans. [3] [10]

There are few or no known examples of serotonergic psychedelics with hallucinogenic effects in humans that do not produce the HTR in animals. [7] [11] [6] [4] One of the only known instances, ALD-52, could be explained by species differences in metabolism. [4] [3] Other possible exceptions, including 2C psychedelics like 2C-B, 2C-I, and 2C-D, may be explained by these agents having relatively low intrinsic activity at the serotonin 5-HT2A receptor and by species differences in sensitivity to HTR elicitation by serotonin 5-HT2A receptor partial agonists. [7] It is also notable that there is an inverted U-shaped dose–response curve for the HTR induced by psychedelics, making proper dosing an important factor in HTR production as well. [3] [12]

False positives

The HTR can be non-specific, with head twitches also produced by some drugs that do not act through serotonin 5-HT2 receptors. [1] [13] Examples of these agents include NMDA receptor antagonists like phencyclidine (PCP), certain benzodiazepines and Z-drugs like estazolam, triazolam, and zopiclone, α2-adrenergic receptor antagonists like yohimbine, muscarinic acetylcholine receptor antagonists like atropine and scopolamine, serotonin 5-HT1A receptor antagonists like WAY-100635 and UH-301, and CB1 receptor antagonists like rimonabant. [1] [3] [6] [4] [2] [13]

Drugs such as the serotonin precursors tryptophan and 5-hydroxytryptophan (5-HTP), serotonin releasing agents (SRAs) like fenfluramine and para-chloroamphetamine (PCA), and other agents like 1-methylpsilocin and 3,4-dimethoxyphenethylamine (DMPEA) stimulate serotonin receptors and can produce head twitches, but are not hallucinogenic in humans. [1] [7] [13] [14] Conversely, while the SRA and mixed entactogen and psychedelic MDA likewise induces the HTR, findings are mixed and conflicting for the SRA and minimally hallucinogenic MDMA. [1]

The preceding findings collectively suggest that while the HTR can be a useful indicator as to whether a compound is likely to display hallucinogenic activity in humans, the induction of a HTR does not necessarily mean that a compound will be hallucinogenic. [15] In relation to this, caution should be exercised when interpreting such results. [15]

Non-hallucinogenic serotonin 5-HT2A receptor agonists

Some serotonin 5-HT2A receptor agonists, such as lisuride, 2-bromo-LSD, ergotamine, 6-fluoro-DET, 6-MeO-DMT, Ariadne, AAZ-A-154 (DLX-001), ITI-1549, 25N-N1-Nap, and IHCH-7086 among others, are thought to be non-hallucinogenic. [16] [1] [6] [4] The HTR is among the only animal behavioral tests that can reliably distinguish between hallucinogenic and non-hallucinogenic serotonin 5-HT2A receptor agonists. [7] [1] [6] It is thought that partial agonism with sufficiently low efficacy underlies the lack of HTR and psychedelic effects with non-hallucinogenic serotonin 5-HT2A receptor agonists. [16] [17] [1] [18]

Serotonin administered by intracerebroventricular injection at high doses produces the HTR in animals. [2] [19] However, serotonin itself is thought to be non-hallucinogenic in humans. [20] [21] [19] [4] [22] The HTR with high doses of serotonin appears to be mediated by more lipophilic N-methylated psychedelic metabolites of serotonin, like bufotenin (N,N-dimethylserotonin). [20] [21] [19] [4] [22]

Modulators of the HTR

While the serotonin 5-HT2A receptor mediates the HTR, other serotonin receptors, including the serotonin 5-HT1A and 5-HT2C receptors, appear to modulate the serotonin 5-HT2A receptor-induced HTR. [1] [23] Serotonin 5-HT1A receptor agonists like 8-OH-DPAT suppress the HTR. [24] [8] [25] [26] In addition, LSM-775, which is a weakly hallucinogenic psychedelic in humans, does not induce the HTR in animals unless the serotonin 5-HT1A receptor is blocked with WAY-100635, suggesting that serotonin 5-HT1A receptor activation masks its psychedelic-like effects. [24] [27] The serotonin 5-HT1A receptor agonist buspirone has been reported to suppress the hallucinogenic effects of serotonergic psychedelics in humans, while the serotonin 5-HT1A receptor antagonist pindolol has been reported to markedly potentiate them. [28] [27] [29] [30]

Serotonin 5-HT2C receptor agonists, for instance Ro 60-0175, CP-809,101, and meta-chlorophenylpiperazine (mCPP), have been reported to suppress the HTR, while serotonin 5-HT2C receptor antagonists, like SB-242084, have been reported to potentiate the HTR. [7] However, in some studies, serotonin 5-HT2C receptor inactivation, by antagonism with SB-242084 or SB-206553 or by receptor knockout, has been reported to diminish the HTR. [7] The reasons for these contradictory findings are unclear. [7] In any case, animal strain differences have been suggested. [7] In addition, the influence of serotonin 5-HT2C receptor signaling on the HTR may be bimodal, with a more recent study finding that the serotonin 5-HT2C receptor antagonist RS-102221 enhanced the HTR at lower doses but inhibited it at higher doses. [25]

A number of other drugs have also been found to modulate the HTR. [3] Monoamine oxidase inhibitors (MAOIs) like harmine, iproniazid, pargyline, clorgyline, and tranylcypromine have been found to potentiate the HTR induced by serotonergic psychedelics and other serotonergic agents without inducing the HTR on their own. [3] [2] This is the case even with psychedelics that are not themselves monoamine oxidase (MAO) substrates. [2] Similarly, the anticonvulsant phenytoin potentiates the HTR. [3]

A variety of other agents, including the β-adrenergic receptor agonist clenbuterol, AMPA receptor antagonists like tezampanel (LY-293558), metabotropic glutamate mGlu2 and mGlu3 receptor agonists like eglumegad and LY-379268, antipsychotics like haloperidol, antihistamines, μ-opioid receptor agonists like morphine, methadone, and pethidine, [31] adenosine A1 receptor agonists like N6-cyclopentyladenosine, and the TAAR1 antagonist EPPTB, have been reported to inhibit the HTR induced by serotonergic psychedelics in animals. [3] [7] [8] Conversely, the metabotropic glutamate mGlu2 and mGlu3 receptor antagonist LY-341495 has been found to potentiate the psychedelic-induced HTR. [7] [8]

Automation

The HTR assay can be very laborious and time-consuming to conduct as it required manual observation. [7] However, semi- and fully-automated forms of the assay, allowing for the possibility of high-throughput screening, have more recently been developed. [7] [32] [33] [34] [35] [36] [37] [38]

History

Table of different HTR-inducing drugs, from the first paper of the HTR as a predictor of psychedelic effects (Corne & Pickering, 1967). Head Twitch Response from different drugs.png
Table of different HTR-inducing drugs, from the first paper of the HTR as a predictor of psychedelic effects (Corne & Pickering, 1967).

The HTR was first described as an effect induced by LSD in 1956. [1] [39] [6] [40] [41] Subsequently, it was described as an effect of large doses of 5-HTP in 1963. [4] [6] [42] In 1967, Corne and Pickering proposed the HTR as a behavioral predictor of hallucinogenic effects in humans. [13] Mediation of the HTR induced by psychedelics like mescaline was proposed in 1982. [7]

Related Research Articles

<span class="mw-page-title-main">Psychedelic drug</span> Hallucinogenic class of psychoactive drug

Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states and a perceived "expansion of consciousness". Also referred to as classic hallucinogens or serotonergic hallucinogens, the term psychedelic is sometimes used more broadly to include various types of hallucinogens, such as those which are atypical or adjacent to psychedelia like salvia and MDMA, respectively.

<span class="mw-page-title-main">Empathogen</span> Class of psychoactive drugs that produce empathic experiences

Empathogens or entactogens are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, relatedness, emotional openness—that is, empathy or sympathy—as particularly observed and reported for experiences with 3,4-methylenedioxymethamphetamine (MDMA). This class of drug is distinguished from the classes of hallucinogen or psychedelic, and amphetamine or stimulants. Major members of this class include MDMA, MDA, MDEA, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB, methylone, mephedrone, GHB, αMT, and αET, MDAI among others. Most entactogens are phenethylamines and amphetamines, although several, such as αMT and αET, are tryptamines. When referring to MDMA and its counterparts, the term MDxx is often used. Entactogens are sometimes incorrectly referred to as hallucinogens or stimulants, although many entactogens such as ecstasy exhibit psychedelic or stimulant properties as well.

<span class="mw-page-title-main">5-Hydroxytryptophan</span> Chemical compound

5-Hydroxytryptophan (5-HTP), used medically as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin.

5-HT<sub>2A</sub> receptor Subtype of serotonin receptor

The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations.

<span class="mw-page-title-main">Serotonin receptor agonist</span> Neurotransmission-modulating substance

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

<span class="mw-page-title-main">5-Fluoro-AMT</span> Chemical compound

5-Fluoro-α-methyltryptamine, also known as PAL-212 or PAL-544, is a putative stimulant, entactogen, and psychedelic tryptamine derivative related to α-methyltryptamine (αMT).

<span class="mw-page-title-main">Quipazine</span> Chemical compound

Quipazine, also known as 1-(2-quinolinyl)piperazine, is a serotonergic drug of the arylpiperazine family and an analogue of 1-(2-pyridinyl)piperazine which is used in scientific research. It was first described in the 1960s and was originally intended as an antidepressant but was never developed or marketed for medical use.

<i>para</i>-Chloroamphetamine Chemical compound

para-Chloroamphetamine (PCA), also known as 4-chloroamphetamine (4-CA), is a serotonin–norepinephrine–dopamine releasing agent (SNDRA) and serotonergic neurotoxin of the amphetamine family. It is used in scientific research in the study of the serotonin system, as a serotonin releasing agent (SRA) at lower doses to produce serotonergic effects, and as a serotonergic neurotoxin at higher doses to produce long-lasting depletions of serotonin.

<span class="mw-page-title-main">Serotonin releasing agent</span> Class of compounds

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, including dopamine and norepinephrine neurons.

<span class="mw-page-title-main">5-Fluoro-DMT</span> Chemical compound

5-Fluoro-N,N-dimethyltryptamine is a tryptamine derivative related to compounds such as 5-bromo-DMT and 5-MeO-DMT. It produces a robust head-twitch response in mice, and hence is a putative serotonergic psychedelic. Fluorination of psychedelic tryptamines either reduces or has little effect on 5-HT2A/C receptor affinity or intrinsic activity, although 6-fluoro-DET is inactive as a psychedelic despite acting as a 5-HT2A agonist, while 4-fluoro-5-methoxy-DMT is a much stronger agonist at 5-HT1A than 5-HT2A.

<span class="mw-page-title-main">2-Bromo-LSD</span> Chemical compound

2-Bromo-LSD, also known as BOL-148 or as bromolysergide, is a derivative of lysergic acid invented by Albert Hofmann, as part of the original research from which the closely related compound LSD was also derived. It is a non-hallucinogenic serotonin 5-HT2A receptor partial agonist, as well as acting at other targets, with psychoplastogenic and antidepressant-like effects in animals.

<span class="mw-page-title-main">25CN-NBOH</span> Chemical compound

25CN-NBOH is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 at the University of Copenhagen. This compound is notable as one of the most selective agonist ligands for the 5-HT2A receptor yet discovered, with a pKi of 8.88 at the human 5-HT2A receptor and with 100x selectivity for 5-HT2A over 5-HT2C, and 46x selectivity for 5-HT2A over 5-HT2B. A tritiated version of 25CN-NBOH has also been accessed and used for more detailed investigations of the binding to 5-HT2 receptors and autoradiography.

<span class="mw-page-title-main">1-Methylpsilocin</span> Chemical compound

1-Methylpsilocin (developmental code names CMY, CMY-16) is a tryptamine derivative developed by Sandoz which acts as a selective agonist of the serotonin 5-HT2C receptor (IC50Tooltip half-maximal inhibitory concentration of 12 nM, vs. 633 nM at 5-HT2A), and an inverse agonist at 5-HT2B (Ki of 38 nM). While 1-methylpsilocin does have higher affinity for 5-HT2C than 5-HT2A, it does produce a head-twitch response in mice that is dependent on 5-HT2A, so it is not entirely free of effects on 5-HT2Ain vivo. In contrast to psilocin, 1-methylpsilocin did not activate 5-HT1A receptors in mice.

A trip killer, or hallucinogen antidote, is a drug that aborts or reduces the effects of a hallucinogenic drug experience. As there are different types of hallucinogens that work in different ways, there are different types of trip killers. They can completely block or reduce the effects of hallucinogens or they can simply provide anxiety relief and sedation. Examples of trip killers, in the case of serotonergic psychedelics, include serotonin receptor antagonists, like antipsychotics and certain antidepressants, and benzodiazepines. Trip killers are sometimes used by recreational psychedelic users as a form of harm reduction to manage so-called bad trips, for instance difficult experiences with prominent anxiety. They can also be used clinically to manage effects of hallucinogens, like anxiety and psychomotor agitation, for instance in the emergency department.

ITI-1549 is a putatively non-hallucinogenic serotonin 5-HT2A receptor agonist which is under development for the treatment of mood disorders and other psychiatric disorders. In addition to acting at the serotonin 5-HT2A receptor, it is also an antagonist of the serotonin 5-HT2B receptor and an agonist of the serotonin 5-HT2C receptor. The drug's route of administration has not been specified.

<span class="mw-page-title-main">6-MeO-DMT</span> Non-hallucinogenic 5-HT2A agonist

6-MeO-DMT, or 6-methoxy-N,N-dimethyltryptamine, also known as 6-OMe-DMT, is a serotonergic drug of the tryptamine family. It is the 6-methoxy derivative of the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and is a positional isomer of the serotonergic psychedelic 5-MeO-DMT.

<span class="mw-page-title-main">6-MeO-isoDMT</span> Serotonergic psychoplastogen

6-MeO-isoDMT, or 6-OMe-isoDMT, also known as 6-methoxy-N,N-dimethylisotryptamine, is a serotonin 5-HT2A receptor agonist, putative serotonergic psychedelic, and psychoplastogen of the isotryptamine group. It is the isotryptamine analogue of the psychedelic 5-MeO-DMT and is a positional isomer of the non-hallucinogenic psychoplastogen 5-MeO-isoDMT.

isoDMT Serotonergic drug

isoDMT, also known as N,N-dimethylisotryptamine, is a putatively non-hallucinogenic serotonin 5-HT2A receptor agonist and psychoplastogen of the isotryptamine group. It is the isotryptamine homologue of dimethyltryptamine (DMT), a more well-known serotonergic psychedelic of the tryptamine family, and represents a small structural modification of DMT.

<span class="mw-page-title-main">Ibogainalog</span> Serotonergic psychedelic

Ibogainalog (IBG), also known as 9-methoxyibogaminalog, is a serotonergic psychedelic and psychoplastogen related to ibogaine but with a simplified chemical structure.

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  30. ↑ Strassman RJ (1996). "Human psychopharmacology of N,N-dimethyltryptamine". Behav Brain Res. 73 (1–2): 121–124. doi:10.1016/0166-4328(96)00081-2. PMID   8788488.
  31. ↑ Salinsky LM, Merritt CR, Zamora JC, Giacomini JL, Anastasio NC, Cunningham KA (2023). "μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges". Front Pharmacol. 14: 1239159. doi: 10.3389/fphar.2023.1239159 . PMC   10598667 . PMID   37886127.
  32. ↑ Halberstadt AL, Geyer MA (June 2013). "Characterization of the head-twitch response induced by hallucinogens in mice: detection of the behavior based on the dynamics of head movement". Psychopharmacology (Berl). 227 (4): 727–739. doi:10.1007/s00213-013-3006-z. PMC   3866102 . PMID   23407781.
  33. ↑ de la Fuente Revenga M, Shin JM, Vohra HZ, Hideshima KS, Schneck M, Poklis JL, González-Maeso J (October 2019). "Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo". Sci Rep. 9 (1): 14247. doi:10.1038/s41598-019-49913-4. PMC   6776537 . PMID   31582824.
  34. ↑ de la Fuente Revenga M, Vohra HZ, González-Maeso J (January 2020). "Automated quantification of head-twitch response in mice via ear tag reporter coupled with biphasic detection". J Neurosci Methods. 334: 108595. doi:10.1016/j.jneumeth.2020.108595. PMC   7363508 . PMID   31954738.
  35. ↑ Halberstadt AL (May 2020). "Automated detection of the head-twitch response using wavelet scalograms and a deep convolutional neural network". Sci Rep. 10 (1): 8344. Bibcode:2020NatSR..10.8344H. doi:10.1038/s41598-020-65264-x. PMC   7239849 . PMID   32433580.
  36. ↑ Glatfelter GC, Chojnacki MR, McGriff SA, Wang T, Baumann MH (May 2022). "Automated Computer Software Assessment of 5-Hydroxytryptamine 2A Receptor-Mediated Head Twitch Responses from Video Recordings of Mice". ACS Pharmacol Transl Sci. 5 (5): 321–330. doi:10.1021/acsptsci.1c00237. PMC   9112414 . PMID   35592434.
  37. ↑ Jaster AM, González-Maeso J (2023). "Automated Detection of Psychedelic-Induced Head-Twitch Response in Mice". Schizophrenia. Methods Mol Biol. Vol. 2687. pp. 65–76. doi:10.1007/978-1-0716-3307-6_6. ISBN   978-1-0716-3306-9. PMID   37464163.
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  39. ↑ McClure-Begley TD, Roth BL (June 2022). "The promises and perils of psychedelic pharmacology for psychiatry". Nat Rev Drug Discov. 21 (6): 463–473. doi:10.1038/s41573-022-00421-7. PMID   35301459.
  40. ↑ Winter CA, Flataker L (June 1956). "Effects of lysergic acid diethylamide upon performance of trained rats". Proc Soc Exp Biol Med. 92 (2): 285–289. doi:10.3181/00379727-92-22453. PMID   13350323.
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