Dimethyltryptamine (DMT) and ibogaine elicit membrane effects in HEK cells transiently transfected with the human 5-HT2A receptor.

Psychedelics like DMT and ibogaine activate the 5-HT2A receptor, a G protein-coupled receptor, to produce therapeutic effects. Naturally occurring genetic variations (SNPs) in this receptor alter its function and drug responsiveness. Using whole-cell electrophysiology on HEK cells expressing either the normal or a mutated (I197V) human 5-HT2AR, membrane currents were observed in both genotypes with both drugs, but not in cells lacking the receptor, confirming the responses depend on 5-HT2AR activation. The I197V mutation shortened the DMT response duration without affecting amplitude. These findings demonstrate that 5-HT2AR-transfected HEK cells can be used to test novel compounds and evaluate SNP effects on drug-induced ion currents.

Study at a glance

Abstract

Psychedelics show promise in treating psychiatric disorders. Therapeutic effects appear to involve activation of the 5-Hydroxytryptamine 2A receptor (5-HT2AR), a G protein-coupled receptor (GPCR). Several SNPs of the 5-HT2AR naturally occur, which are associated with differences in receptor function and altered responsiveness to treatments. New compounds suspected to act at the 5-HT2AR are actively being generated. HEK cells are not commonly used to study membrane effects induced by agonists of GPCRs. In this study, for the first time, membrane actions of two psychedelics, dimethyltryptamine (DMT) and ibogaine on HEK cells transiently transfected with either the human wildtype (WT) or the human I197V mutated 5-HT2AR were investigated using whole-cell electrophysiology. Membrane effects were observed in both genotypes and with both drugs in most cells, while no responses were observed in non-transfected HEK cells suggesting that responses were due to 5-HT2AR activation. In HEK cells transfected with the I197V SNP, a significantly shorter duration of the DMT response was observed, however there were no differences in drug-elicited amplitudes between drug or receptor genotype. I-V curves showed a significant effect of drug exposure for both DMT and ibogaine at the highest concentration evaluated. Taken together, our data show transfection of the 5-HT2AR, a GPCR, in HEK cells is able to activate downstream ion channels following exposure to two different 5-HT2AR agonists. Accordingly, investigations of novel compounds suspected to act at 5-HT2ARs can include examination of elicitation of ionic currents in 5-HT2AR transfected HEK cells, and drug effects at SNPs can also be evaluated.