The hallucinogenic compound DOI triggers a head-twitch response in mice, which is considered a behavioral proxy for hallucinogenic effects in humans. This response depends on the 5-HT2A serotonin receptor, but the study shows it is also strongly modulated by the 5-HT2C receptor. Mice lacking the 5-HT2C receptor showed about 50% fewer head twitches after DOI administration. Blocking the 5-HT2C receptor with specific antagonists reduced the head-twitch response by at least half in two different mouse strains. Differences in the 5-HT2A receptor did not explain strain variations in the response, suggesting 5-HT2C receptor signaling or other modulators are involved. The finding calls for a reassessment of how hallucinogens work through serotonin receptors.
Recent small but well-controlled clinical trials indicate that serotonergic psychedelics such as psilocybin and LSD show promise for treating psychiatric disorders like treatment-resistant depression. Neuroimaging studies reveal dynamic effects on brain activity and connectivity across neural systems, leading to testable hypotheses about mechanisms underlying psychedelic effects and therapeutic benefits. Despite evidence that brain serotonin 5-HT2A receptors are central to these effects, lingering questions about molecular neuropharmacology remain. This chapter discusses these questions in the context of preclinical experimental approaches for studying mechanisms of action of classic and new serotonergic psychedelics.
A psychedelic tryptamine, DPT, completely prevented sound-induced seizures in a mouse model of fragile X syndrome at a 10 mg/kg dose but not at lower doses. Although DPT activates several serotonin receptors in the lab, blocking those receptors did not stop its anti-seizure effect, nor did blocking sigma1 receptors. The anti-seizure action appears independent of DPT's psychedelic properties. However, high doses of DPT caused convulsions on their own, indicating complex, dose-dependent effects.
A newly developed electromagnetic signal derived from the serotonin 2 receptor agonist DOI, converted into a playable WAV file, significantly reduced the head-twitch response in mice—a behavioral proxy for psychedelic effects—when administered alongside DOI. The effect was specific: a scrambled version of the signal did not alter the response. The findings suggest that defined electromagnetic signals could potentially modulate the psychoactive effects of serotonergic psychedelics, offering a new strategy to mitigate the heightened anxiety associated with psychedelic therapy. The authors discuss possible mechanisms and connections to prior work showing electromagnetic signals' efficacy in treating pain and cancer.