RT Journal Article
SR Electronic
T1 Tolerance and Cross-Tolerance to Head Twitch Behavior Elicited by Phenethylamine- and Tryptamine-Derived Hallucinogens in Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 485
OP 491
DO 10.1124/jpet.114.219337
VO 351
IS 3
A1 Douglas A. Smith
A1 Jessica M. Bailey
A1 Diarria Williams
A1 William E. Fantegrossi
YR 2014
UL http://jpet.aspetjournals.org/content/351/3/485.abstract
AB The serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor is a potential therapeutic target to a host of neuropsychiatric conditions, but agonist actions at this site are linked to abuse-related hallucinogenic effects that may limit therapeutic efficacy of chronic drug administration. Tolerance to some effects of hallucinogens has been observed in humans and laboratory animals, but the understanding of tolerance and cross-tolerance between distinct structural classes of hallucinogens is limited. Here, we used the drug-elicited head twitch response (HTR) in mice to assess the development of tolerance and cross-tolerance with two phenethylamine-derived [DOI (2,5-dimethoxy-4-iodoamphetamine) and 2C-T-7 (2,5-dimethoxy-4-propylthiophenethylamine)] and two tryptamine-derived [DPT (N,N-dipropyltryptamine) and DIPT (N,N-diisopropyltryptamine)] drugs with agonist affinity for 5-HT2A receptors. Tolerance developed to HTR elicited by daily DOI or 2C-T-7, but not to HTR elicited by DPT or DIPT. DOI-elicited tolerance was not surmountable with dose, and a similar insurmountable cross-tolerance was evident when DOI-tolerant mice were tested with various doses of 2C-T-7 or DPT. These studies suggest that the use of phenethylamine-derived hallucinogens as therapeutic agents may be limited not only by their abuse potential, but also by the rapid development of tolerance that would likely be maintained even if a patient were switched to a different 5-HT2A agonist medication from a distinct structural class. However, these experiments also imply that tryptamine-derived hallucinogens might have a reduced potential for tolerance development, compared with phenethylamine-derived 5-HT2A agonists, and might therefore be more suitable for chronic administration in a therapeutic context.