The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen
Clinton E. Canal, U. B. Olaghere da Silva, Paul J Gresch, Erin E. Watt, Elaine Sanders‐bush, D. Airey
Psychopharmacology February 19, 2010 DOI: 10.1007/s00213-010-1784-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice (5-HT2C receptor knockout and wild-type littermates; C57BL/6J and DBA/2J strains) |
| Topics | Serotonin |
| Citations | 111 |
| Key findings | The head-twitch response to DOI in mice is strongly modulated by 5-HT2C receptor activity, as shown by approximately 50% reduction in knockout mice and at least 50% reduction with antagonists. |
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.
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- Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways Current Topics in Behavioral Neurosciences 2017
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- Psychedelic Drugs in Biomedicine TIPS - Trends in Pharmacological Sciences September 22, 2017
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Cites 19
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Agonist-Trafficking and Hallucinogens Current Medicinal Chemistry March 1, 2009
- Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice Psychopharmacology January 11, 2005
- Hallucinogens. Pharmacology & Therapeutics February 1, 2004
- 5-HT_2A and 5-HT_2C Receptors Exert Opposing Effects on Locomotor Activity in Mice Neuropsychopharmacology July 1, 2009
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