Behavioral arrest and a characteristic slow waveform are hallmark responses to selective 5-HT2A receptor activation
April Contreras, Matthew Khumnark, Rochelle M. Hines, Dustin J. Hines
Scientific Reports January 21, 2021 DOI: 10.1038/s41598-021-81552-6 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study in mice Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | 25I-NBOH Nicotine |
| Measures | electroencephalogram (EEG), head twitch response (HTR) |
| Topics | Serotonin |
| Key findings | The authors report that 25I-NBOH produces behavioral arrest preceding the head twitch response by a precise interval, with matching EEG waveforms (Phase 1 at 3.5–4.5 Hz and Phase 2 at 2.5–3.2 Hz), and argue that behavioral arrest and these slow waveforms are key hallmarks of 5-HT2AR activation alongside the HTR. Nicotine pretreatment attenuated HTR and Phase 2 but increased behavioral arrest and Phase 1. |
Abstract
Perception, emotion, and mood are powerfully modulated by serotonin receptor (5-HTR) agonists including hallucinogens. The 5-HT2AR subtype has been shown to be central to hallucinogen action, yet the precise mechanisms mediating the response to 5-HT2AR activation remain unclear. Hallucinogens induce the head twitch response (HTR) in rodents, which is the most commonly used behavioral readout of hallucinogen pharmacology. While the HTR provides a key behavioral signature, less is known about the meso level changes that are induced by 5-HT2AR activation. In response to administration of the potent and highly selective 5-HT2AR agonist 25I-NBOH in mice, we observe a disorganization of behavior which includes frequent episodes of behavioral arrest that consistently precede the HTR by a precise interval. By combining behavioral analysis with electroencephalogram (EEG) recordings we describe a characteristic pattern composed of two distinctive EEG waveforms, Phase 1 and Phase 2, that map onto behavioral arrest and the HTR respectively, with the same temporal separation. Phase 1, which underlies behavioral arrest, is a 3.5–4.5 Hz waveform, while Phase 2 is slower at 2.5–3.2 Hz. Nicotine pretreatment, considered an integral component of ritualistic hallucinogen practices, attenuates 25I-NBOH induced HTR and Phase 2 waveforms, yet increases behavioral arrest and Phase 1 waveforms. Our results suggest that in addition to the HTR, behavioral arrest and characteristic meso level slow waveforms are key hallmarks of the response to 5-HT2AR activation. Increased understanding of the response to serotonergic hallucinogens may provide mechanistic insights into perception and hallucinations, as well as regulation of mood.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 10
- Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications International Journal of Molecular Sciences November 16, 2022
- Psilocin acutely alters sleep-wake architecture and cortical brain activity in laboratory mice Translational Psychiatry February 23, 2022
- Antidepressant- and anxiolytic-like activities and acute toxicity evaluation of the Psilocybe cubensis mushroom in experimental models in mice. Journal of Ethnopharmacology February 10, 2024
- LSD's rapid antidepressant effects are modulated by 5-HT2B receptors. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie July 16, 2025
- The novel non-hallucinogenic compound DM506 (3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole) induces sedative- and anxiolytic-like activity in mice by a mechanism involving 5-HT2A receptor activation. European Journal of Pharmacology March 5, 2024
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