Faculty Collaboration Database

Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice. ACS Chem Neurosci 2024 Dec 18;15(24):4458-4477

Date

12/05/2024

Pubmed ID

39636099

Pubmed Central ID

PMC12745965

DOI

10.1021/acschemneuro.4c00513

Scopus ID

2-s2.0-85211348154 (requires institutional sign-in at Scopus site)   10 Citations

Abstract

5-methoxy-N,N-dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its N-alkyl, N-allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the compounds, 2) to characterize in vitro functional activities at serotonin (5-HT) 2A receptors (5-HT_2A) and 1A receptors (5-HT_1A), and 3) to examine the influence of 5-HT_1A on 5-HT_2A-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro receptor binding and functional assays showed that all 5-MeO-DMT analogs bind with high affinity and activate multiple targets (e.g., 5-HT receptor subtypes, alpha adrenergic receptors), including potent effects at 5-HT_2A and 5-HT_1A. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED₅₀ range = 0.2-1.8 mg/kg) and maximal effects (E_max range = 20-60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED₅₀ range = 3.2-20.6 mg/kg). 5-HT_2A antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT_1A antagonist pretreatment enhanced HTRs. In general, N,N-dialkyl and N-isopropyl derivatives displayed HTR activity, while the N-methyl, N-ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT_1A unmasked latent HTR activity for the N-ethyl analog and markedly increased maximal responses for other HTR-active compounds (40-90 HTRs/30 min), supporting the notion that 5-HT_1A agonist activity can dampen 5-HT_2A-mediated HTRs. Suppression of 5-HT_2A-mediated HTRs by 5-HT_1A only occurred after high 5-MeO-DMT doses, suggesting involvement of other receptors in modulating psychedelic-like effects. Overall, our findings provide key information about the receptor target profiles for 5-MeO-DMT analogs, the structure-activity relationships for inducing psychedelic-like effects, and the critical role of 5-HT_1A agonism in modulating acute psychoactive effects of 5-HT_2A agonists.

Author List

Glatfelter GC, Clark AA, Cavalco NG, Landavazo A, Partilla JS, Naeem M, Golen JA, Chadeayne AR, Manke DR, Blough BE, McCorvy JD, Baumann MH

Author

John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Behavior, Animal
Hallucinogens
Head Movements
Humans
Male
Methoxydimethyltryptamines
Mice
Mice, Inbred C57BL
Receptor, Serotonin, 5-HT1A
Receptor, Serotonin, 5-HT2A