5-Methoxy-α-methyltryptamine (5-MeO-AMT), a tryptamine derivative, induces head-twitch responses in mice through the activation of serotonin receptor 2a in the prefrontal cortex

• Published in: Behavioural brain research Vol. 359; pp. 828 - 835
• Main Authors: Abiero, Arvie, Botanas, Chrislean Jun, Sayson, Leandro Val, Custodio, Raly James, de la Peña, June Bryan, Kim, Mikyung, Lee, Hyun Jun, Seo, Joung-Wook, Ryu, In Soo, Chang, Cho Min, Yang, Ji Seul, Lee, Yong Sup, Jang, Choon-Gon, Kim, Hee Jin, Cheong, Jae Hoon
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2019
• Subjects: 5-Methoxy-a-methyltryptamine; Animals; Conditioned place preference; Conditioning, Operant - drug effects; Dose-Response Relationship, Drug; Gene Expression Regulation - drug effects; Head Movements - drug effects; Head-twitch response; Ketanserin - pharmacology; Locomotion - drug effects; Male; Mice; Mice, Inbred C57BL; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Protein Kinases - genetics; Protein Kinases - metabolism; Receptor, Serotonin, 5-HT2A - genetics; Receptor, Serotonin, 5-HT2A - metabolism; RNA, Messenger - metabolism; Self Administration; Serotonin - analogs & derivatives; Serotonin - pharmacology; Serotonin Agents - pharmacology; Serotonin receptor 2a; Self-administration; Serotonin receptor 2a; Conditioned place preference; 5-Methoxy-a-methyltryptamine; Head-twitch response
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2018.07.020

•5-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-γ phosphorylation.•5-MeO-AMT did not induce sensitization, CPP, or SA. 5-Methoxy-α-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-γ), and extracellular signal-regulated kinases 1/2 (ERK1/2), in addition to PKC-γ 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-γ 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.