Journal
PSYCHOPHARMACOLOGY
Volume 209, Issue 2, Pages 163-174Publisher
SPRINGER
DOI: 10.1007/s00213-010-1784-0
Keywords
Serotonin 2A receptor (5-HT2A); Serotonin 2C receptor (5-HT2C); Hallucinogens; Head-twitch response (HTR); Phospholipase C (PLC); Phospholipase A (PLA)
Categories
Funding
- National Institute of Mental Health's Psychoactive Drug Screening Program (NIMH PDSP) [NO1MH32004]
- [P50 MH78028]
- [DA005181]
- [T32 MH0652150]
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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, G alpha(q) or G alpha(i/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.
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