LAUSR

Highlights5‐MeO‐AMT is a tryptamine derivative.5‐MeO‐AMT induces the head‐twitch response in mice.Ketanserin blocks the 5‐MeO‐AMT‐induced HTR.5‐MeO‐AMT alters 5‐HTR2a mRNA level and induces PKC‐&ggr; phosphorylation.5‐MeO‐AMT did not induce sensitization, CPP, or SA. Abstract 5‐Methoxy‐&agr;‐methyltryptamine (5‐MeO‐AMT) is a tryptamine derivative that is used recreationally because of its reported hallucinogenic and mood elevating effects. Studies suggest that the psychopharmacological effects of tryptamines involve serotonin receptor 2a (5‐HTR2a) activation in the brain. The head‐twitch response (HTR) is widely used as a behavioral correlate for assessing 5‐HTR2a agonist activity of a drug. Thus, we investigated whether 5‐MeO‐AMT induces HTR in mice and explored its mechanism of action. 5‐MeO‐AMT (0.3, 1, 3, 10 mg/kg) was administered once a day for 7 days, and the HTR was measured after 1 day (acute) and 7 days (repeated) of administration. Another cohort of mice was treated with 5‐HTR2a antagonist ketanserin (KS) before 5‐MeO‐AMT administration. We measured 5‐HTR2a and 5‐HTR2c mRNA levels in the prefrontal cortex of the mice treated acutely or repeatedly with 5‐MeO‐AMT. We performed western blotting to determine the effects of the drug on the expression of G protein (Gq/11), protein kinase C gamma (PKC‐&ggr;), and extracellular signal‐regulated kinases 1/2 (ERK1/2), in addition to PKC‐&ggr; and ERK1/2 phosphorylation. Additionally, we evaluated potential rewarding and reinforcing effects of 5‐MeO‐AMT using locomotor sensitization, conditioned place preference (CPP), and self‐administration (SA) paradigms. Acute 5‐MeO‐AMT administration elicited the HTR, while repeated administration resulted in tolerance. KS blocked the 5‐MeO‐AMT‐induced HTR. 5‐MeO‐AMT increased 5‐HTR2a mRNA levels and induced PKC‐&ggr; phosphorylation in the prefrontal cortex. 5‐MeO‐AMT did not induce locomotor sensitization, CPP, or SA. This study shows that 5‐MeO‐AMT induces HTR through 5‐HTR2a activation in the prefrontal cortex, and may have low potential for abuse.