Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark. Electronic address: kak1@sund.ku.dk.
2 papers in the library · 7 citations · publishing 2025
The synthetic psychedelic 25CN-NBOH, which binds strongly to serotonin type 2A receptors, has a dual effect on neurons in the mouse medial prefrontal cortex. Acute application of a high concentration (10 µM) increased the frequency of spontaneous excitatory postsynaptic currents, an effect dependent on serotonin 2A receptor activation and not seen with chronic exposure or a lower concentration (200 nM). However, both concentrations suppressed the firing rate of pyramidal neurons after acute and one-hour exposure. This suppression was independent of serotonin 2A receptors but mediated by M-current channels, as blocking M-currents reversed it. The compound thus enhances excitatory transmission while reducing overall excitability, revealing complex cellular actions that may underlie its therapeutic effects.
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.