Head-twitch response

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]

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 various 2C psychedelics like 2C-B, 2C-I, and 2C-D, as well as the phenylpiperazine TFMPP, 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 (mice being more sensitive than rats).[7][1] It is additionally 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

See also: 5-Hydroxytryptophan § Psychedelic effects, and Serotonin releasing agent § Psychedelic-like effects

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][15]

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 the HTR does not necessarily mean that a compound will be hallucinogenic.[16] In relation to this, caution should be exercised when interpreting such results.[16]

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.[17][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.[17][18][1][19]

Serotonin administered by intracerebroventricular injection at high doses produces the HTR in animals.[2][20] However, serotonin itself is thought to be non-hallucinogenic in humans.[21][22][20][4][23] 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).[21][22][20][4][23]

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][24] Serotonin 5-HT1A receptor agonists like 8-OH-DPAT suppress the HTR.[25][8][26][27] 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.[25][28] 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.[29][28][30][31]

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.[26]

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,[32] 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][33][34][35][36][37][38][39]

History

Table of different HTR-inducing drugs, from the first paper of the HTR as a predictor of psychedelic effects (Corne & Pickering, 1967).[13]

The HTR was first described as an effect induced by LSD in 1956.[1][40][6][41][42] Subsequently, it was described as an effect of large doses of 5-HTP in 1963.[4][6][43] 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]

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