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Tolerance and cross‐tolerance to behavioral effects of phenethylamine‐ and tryptamine‐derived hallucinogens in mice (661.2)
Author(s) -
Smith Douglas,
Williams Diarra,
Fantegrossi William
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.661.2
Subject(s) - hallucinogen , tryptamines , cross tolerance , tryptamine , pharmacology , agonist , phenethylamine , serotonin , phenethylamines , drug tolerance , 5 ht receptor , chemistry , receptor , medicine , morphine
Tolerance refers to a decrease in effect(s) of a drug due to repeated administration, and develops rapidly to psychoactive effects of some hallucinogens in man. Tolerance to various effects of hallucinogenic drugs can also be readily induced in laboratory rodents, and is presumably mediated by downregulation of serotonin 5‐HT2A receptors. The hallucinogen‐induced head twitch response (HTR) in mice is a reliable rodent model for psychedelic effects because it is mediated by agonist activity at 5‐HT2A receptors, but the role of tolerance in HTR remains somewhat controversial. In these studies, two phenethylamine hallucinogens (2,5‐dimethoxy‐4‐iodoamphetamine [DOI] and 2,5‐dimethoxy‐4‐ n ‐propylthiophenethylamine [2C‐T‐7]) and two tryptamine hallucinogens (dipropyltryptamine [DPT] and diisopropyltryptamine [DIPT]) were administered to male NIH Swiss mice to determine dose‐effect functions for HTR. The most effective dose of each compound was then selected for repeated administration to assess the development of tolerance to the HTR. Finally, mice received daily treatment with DOI for 3 days, then were substituted with different doses of DOI, 2C‐T‐7, DPT or DIPT the next day to assess surmountability of tolerance and cross‐tolerance among drugs. Repeated administration of the phenethylamines ‐ but not the tryptamines ‐ resulted in rapid tolerance to HTR in mice which was not surmountable with increased dose. Although the tryptamines did not induce tolerance to HTR with repeated administration, cross‐tolerance to HTR elicited by DPT was observed in mice previously treated with DOI, and this cross‐tolerance was not surmountable with increased DPT dose. Explanations for these distinct effects of phenethyltamine‐ and tryptamine‐based hallucinogens may include the involvement of 5‐HT2C receptors (for the phenethylamines) or 5‐HT1A receptors (for the tryptamines.) Grant Funding Source : Supported by RR020146, RR029884, and by an ASPET SURF award to DS