, Volume 209, Issue 2, pp 163–174 | Cite as

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

  • Clinton E. Canal
  • Uade B. Olaghere da Silva
  • Paul J. Gresch
  • Erin E. Watt
  • Elaine Sanders-Bush
  • David C. Airey
Original Investigation



Hallucinogenic 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.


We tested for involvement of 5-HT2C receptors in the HTR induced by DOI.


Comparison 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.


We 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.


Serotonin 2A receptor (5-HT2ASerotonin 2C receptor (5-HT2CHallucinogens Head-twitch response (HTR) Phospholipase C (PLC) Phospholipase A (PLA) 



We thank research assistants Katherine Smith, Dongmei Li, and Jason Abramo for diligent and careful work in the laboratory. The authors report no conflicts of interest. Ki determinations were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # NO1MH32004 (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA.


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Clinton E. Canal
    • 1
    • 2
  • Uade B. Olaghere da Silva
    • 1
  • Paul J. Gresch
    • 1
  • Erin E. Watt
    • 1
  • Elaine Sanders-Bush
    • 1
  • David C. Airey
    • 1
  1. 1.Department of PharmacologyVanderbilt University School of MedicineNashvilleUSA
  2. 2.Department of Medicinal ChemistryUniversity of Florida College of PharmacyGainesvilleUSA

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