title: Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice.
abstract: Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a hallucinogen that acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors. Psilocin is the active metabolite of psilocybin, a hallucinogen that is currently being investigated clinically as a potential therapeutic agent. In the present investigation, we used a combination of genetic and pharmacological approaches to identify the serotonin (5-HT) receptor subtypes responsible for mediating the effects of psilocin on head twitch response (HTR) and the behavioral pattern monitor (BPM) in C57BL/6J mice. We also compared the effects of psilocin with those of the putative 5-HT(2C) receptor-selective agonist 1-methylpsilocin and the hallucinogen and non-selective serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Psilocin, 1-methylpsilocin, and 5-MeO-DMT induced the HTR, effects that were absent in mice lacking the 5-HT(2A) receptor gene. When tested in the BPM, psilocin decreased locomotor activity, holepoking, and time spent in the center of the chamber, effects that were blocked by the selective 5-HT(1A) antagonist WAY-100635 but were not altered by the selective 5-HT(2C) antagonist SB 242,084 or by 5-HT(2A) receptor gene deletion. 5-MeO-DMT produced similar effects when tested in the BPM, and the action of 5-MeO-DMT was significantly attenuated by WAY-100635. Psilocin and 5-MeO-DMT also decreased the linearity of locomotor paths, effects that were mediated by 5-HT(2C) and 5-HT(1A) receptors, respectively. In contrast to psilocin and 5-MeO-DMT, 1-methylpsilocin (0.6-9.6 mg/kg) was completely inactive in the BPM. These findings confirm that psilocin acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors in mice, whereas the behavioral effects of 1-methylpsilocin indicate that this compound is acting at 5-HT(2A) sites but is inactive at the 5-HT(1A) receptor. The fact that 1-methylpsilocin displays greater pharmacological selectivity than psilocin indicates that 1-methylpsilocin represents a potentially useful alternative to psilocybin for development as a potential therapeutic agent.
authors.affiliation: Department of Psychiatry, University of California, La Jolla, CA 92093-0804, USA.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Halberstadt
authors.forename: Liselore
authors.initials: L
authors.lastname: Koedood
authors.forename: Susan B
authors.initials: SB
authors.lastname: Powell
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
mesh_terms: D000818:Animals; D001519:Behavior / Q000187:drug effects*; D006213:Hallucinogens / Q000494:pharmacology*; D008297:Male; D008732:Methoxydimethyltryptamines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D011562:Psilocybin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D006213:Hallucinogens; D008732:Methoxydimethyltryptamines; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D011562:Psilocybin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C009105:psilocin