The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen

Summary

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.

Study at a glance

Abstract

RationaleHallucinogenic serotonin 2A (5-HT2A) receptor partial agonists, such as (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), induce a frontal cortex-dependent head-twitch response (HTR) in rodents, a behavioral proxy of a hallucinogenic response that is blocked by 5-HT2A receptor antagonists. In addition to 5-HT2A receptors, DOI and most other serotonin-like hallucinogens have high affinity and potency as partial agonists at 5-HT2C receptors.ObjectivesWe tested for involvement of 5-HT2C receptors in the HTR induced by DOI.ResultsComparison of 5-HT2C receptor knockout and wild-type littermates revealed an approximately 50% reduction in DOI-induced HTR in knockout mice. Also, pretreatment with either the 5-HT2C receptor antagonist SB206553 or SB242084 eradicated a twofold difference in DOI-induced HTR between the standard inbred mouse strains C57BL/6J and DBA/2J, and decreased the DOI-induced HTR by at least 50% in both strains. None of several measures of 5-HT2A receptors in frontal cortex explained the strain difference, including 5-HT2A receptor density, Gαq or Gαi/o protein levels, phospholipase C activity, or DOI-induced expression of Egr1 and Egr2. 5-HT2C receptor density in the brains of C57BL/6J and DBA/2J was also equivalent, suggesting that 5-HT2C receptor-mediated intracellular signaling or other physiological modulators of the HTR may explain the strain difference in response to DOI.ConclusionsWe conclude that the HTR to DOI in mice is strongly modulated by 5-HT2C receptor activity. This novel finding invites reassessment of hallucinogenic mechanisms involving 5-HT2 receptors.