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.
RNA transcripts encoding the serotonin 5-HT2C receptor undergo editing at up to five specific sites, altering the amino acid sequence. Human brain samples expressed higher levels of edited variants (5-HT2C-VSV and 5-HT2C-VGV) compared with rat brain. Agonist stimulation of nonedited and edited receptors expressed in fibroblasts showed that serotonergic agonists were less potent at the edited receptors. Competition binding experiments revealed a guanine nucleotide-sensitive serotonin high affinity state only for the nonedited receptor, indicating that editing reduces G protein coupling efficiency, primarily by silencing the constitutive activity of the nonedited receptor. These distinctions suggest RNA editing controls physiological signaling at serotonergic synapses.