7.0 KiB
| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| Head-twitch response | 4/5 | https://en.wikipedia.org/wiki/Head-twitch_response | reference | science, encyclopedia | 2026-05-05T07:29:09.145592+00:00 | kb-cron |
Some serotonin 5-HT2A receptor agonists, including lisuride, 2-bromo-LSD (bromolysergide; BOL-148), ergotamine, 6-fluoro-DET, 6-MeO-DMT, Ariadne, zalsupindole (DLX-001; AAZ-A-154), ITI-1549, 25N-N1-Nap, and IHCH-7086 among others, are either non-hallucinogenic or are thought to be non-hallucinogenic in spite of activating the serotonin 5-HT2A receptor. The HTR is among the only animal behavioral tests that can reliably distinguish between hallucinogenic and non-hallucinogenic serotonin 5-HT2A receptor agonists. Although lisuride and other non-hallucinogenic serotonin 5-HT2A receptor agonists do not produce the HTR in rodents, lisuride does produce the HTR in the least shrew, a non-rodent species that is said to be highly sensitive to serotonin 5-HT2A receptor agonists. 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. However, other findings suggest that ergotamine may be non-hallucinogenic due to inability to efficiently cross the blood–brain barrier and peripheral selectivity, while lisuride and 2-bromo-LSD may actually be variably hallucinogenic at sufficiently high doses. Serotonin administered by intracerebroventricular injection at high doses produces the HTR in animals. However, serotonin itself has been considered to be non-hallucinogenic in humans. This would be in accordance with the lack of inherent psychedelic effects with serotonin releasing agents, serotonin reuptake inhibitors, and serotonin precursors in humans. The HTR with high doses of serotonin in animals appears to be mediated by formation of more lipophilic N-methylated psychedelic metabolites of serotonin, like bufotenin (N,N-dimethylserotonin).
=== Others === Surprisingly, the HTR induced by the mescaline-related psychedelic drug methallylescaline (MAL) was blocked by the selective serotonin 5-HT2C receptor antagonist SB-242084 but not by the serotonin 5-HT2A receptor antagonist ketanserin. This was in contrast to the case of the 2C and BOx psychedelic BOD (β-methoxy-2C-D) in the same study, for which both ketanserin and SB-242084 blocked the HTR. These findings suggest an involvement of the serotonin 5-HT2C receptor and not the serotonin 5-HT2A receptor in the psychedelic-like effects of methallylescaline in rodents. In addition, they suggest that different psychedelics may differentially activate the serotonin 5-HT2A and 5-HT2C receptors to produce their psychedelic-like effects.
== Modulators of the head-twitch response == 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. Serotonin 5-HT1A receptor agonists like 8-OH-DPAT suppress the HTR, while serotonin 5-HT1A receptor antagonists can augment it. 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. 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. However, paradoxically, whereas the serotonin 5-HT1A receptor full agonist 8-OH-DPAT suppresses the HTR induced by 5-hydroxytryptophan (5-HTP) or DOI, buspirone, a serotonin 5-HT1A receptor partial agonist, has been shown to enhance the HTR induced by 5-HTP plus pargyline. The possible influence of serotonin 5-HT2B receptor signaling on the HTR has been little-studied and is largely unknown. However, a subsequent study found that the highly selective 5-HT2B receptor antagonist RS-127445 diminished the HTR induced by LSD in rats but not in mice. 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. 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. The reasons for these contradictory findings are unclear. In any case, animal strain differences have been suggested. 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. A number of other drugs have also been found to modulate the HTR. 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. 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. In contrast to MAOIs, serotonin reuptake inhibitors (SRIs), including citalopram, fluoxetine, fluvoxamine, and imipramine, do not affect the HTR induced by DOI. Conversely, serotonin transporter (SERT) knockout greatly reduces or even eliminates the psychedelic-induced HTR. This may be due to elevated serotonin levels and decreased serotonin 5-HT2A receptor expression. Unlike SRIs, chronic administration of serotonin–norepinephrine reuptake inhibitors (SNRIs) has been found to decrease the DOI-induced HTR. The anticonvulsant phenytoin potentiates the HTR. NMDA receptor antagonists like phencyclidine (PCP), ketamine, and dizocilpine (MK-801) have been found to enhance the DOI-induced HTR as well. 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, adenosine A1 receptor agonists like N6-cyclopentyladenosine, and the TAAR1 antagonist EPPTB, have been reported to inhibit the HTR induced by serotonergic psychedelics and/or other serotonergic agents in animals. Conversely, the metabotropic glutamate mGlu2 and mGlu3 receptor antagonist LY-341495 has been found to potentiate the psychedelic-induced HTR. Selective dopamine D3 receptor agonists like WC-44 and WW-III-55 suppress the HTR induced by DOI. Serotonin depletion has been found to potentiate the HTR. This appears to be related to increased postsynaptic serotonin 5-HT2 receptors.
== History ==