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

Rationale Hallucinogenic serotonin 2A (5-HT 2A ) 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-HT 2A receptor antagonists. In addition to 5-HT 2A receptors, DOI and most other serotonin-like hallucinogens have high affinity and potency as partial agonists at 5-HT 2C receptors. Objectives We tested for involvement of 5-HT 2C receptors in the HTR induced by DOI. Results Comparison of 5-HT 2C receptor knockout and wild-type littermates revealed an approximately 50% reduction in DOI-induced HTR in knockout mice. Also, pretreatment with either the 5-HT 2C 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-HT 2A receptors in frontal cortex explained the strain difference, including 5-HT 2A receptor density, Gα q or Gα i/o protein levels, phospholipase C activity, or DOI-induced expression of Egr1 and Egr2 . 5-HT 2C receptor density in the brains of C57BL/6J and DBA/2J was also equivalent, suggesting that 5-HT 2C receptor-mediated intracellular signaling or other physiological modulators of the HTR may explain the strain difference in response to DOI. Conclusions We conclude that the HTR to DOI in mice is strongly modulated by 5-HT 2C receptor activity. This novel finding invites reassessment of hallucinogenic mechanisms involving 5-HT 2 receptors.