Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice

• Published in: Journal of psychopharmacology (Oxford) 2011-11, Vol.25 (11), p.1548-1561
• Main Authors: Halberstadt, Adam L, Koedood, Liselore, Powell, Susan B, Geyer, Mark A
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Animal behavior; Animals; Anxiety disorders. Neuroses; Behavior - drug effects; Biological and medical sciences; Genetics; Hallucinogens; Hallucinogens - pharmacology; Male; Medical sciences; Methoxydimethyltryptamines - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity - drug effects; Neuropharmacology; Obsessive-compulsive disorders; Pharmacology. Drug treatments; Piperazines - pharmacology; Psilocybin - analogs & derivatives; Psilocybin - pharmacology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Pyridines - pharmacology; Receptors, Serotonin - genetics; Receptors, Serotonin - metabolism; Rodents; Serotonin; Serotonin Antagonists - pharmacology
• ISSN: 0269-8811; 1461-7285
• DOI: 10.1177/0269881110388326

Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a hallucinogen that acts as an agonist at 5-HT1A, 5-HT2A, and 5-HT2C 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-HT2C 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-HT2A 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-HT1A antagonist WAY-100635 but were not altered by the selective 5-HT2C antagonist SB 242,084 or by 5-HT2A 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-HT2C and 5-HT1A 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-HT1A, 5-HT2A, and 5-HT2C receptors in mice, whereas the behavioral effects of 1-methylpsilocin indicate that this compound is acting at 5-HT2A sites but is inactive at the 5-HT1A 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.