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.
Highlights
Serotonin is both a hormone and neuromodulatory neurotransmitter that is involved in executive function, emotions and perceptions
We demonstrate that the highly potent and specific 5-HT2AR agonist 25I-NBOH induces a disorganization of behavior marked by behavioral arrest and a robust head-twitch response (HTR)
Despite no overall change in distance traveled or average speed, our results show that 25I-NBOH activation of 5-HT2ARs affects the number of stops made in the open field, which were characterized by an absence of visual survey or grooming behaviors
Summary
Serotonin is both a hormone and neuromodulatory neurotransmitter that is involved in executive function, emotions and perceptions. Low frequency band activity is characteristic of sleep, with high amplitude δ (0.5–4 Hz) being characteristic of slow wave sleep, and θ (4–8 Hz) characteristic of REM or subconscious states It remains unclear what this rise in low frequency bands following activation of 5-HT2AR reflects at the meso level. In Mesoamerican cultures, hallucinogens have been extensively used in ritualistic and religious practices since pre-Columbian times[42] This long history of use resulted in the accumulation of knowledge about the effects of hallucinogens, and skill in their use[43]. The especially high nicotine content of wild tobacco is thought to enhance the effects of hallucinogens, with respect to the entheogenic e ffects[44] Despite this long history of combined use, relatively little research has examined hallucinogen activation of 5-HT2ARs in conjunction with nicotine’s action on nicotinic acetylcholine receptors. We demonstrate that pretreatment with nicotine strikingly attenuates both the HTR and P2, while increasing the duration of episodes of behavioral arrest as well as the occurrence of P1 waveforms
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