The Selective 5HT2A Receptor Agonist, 25CN-NBOH Exerts Excitatory and Inhibitory Cellular Actions on Mouse Medial Prefrontal Cortical Neurons.

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.

Study at a glance

Abstract

Psychedelic compounds have gained renewed interest due to their rapid and long-lasting therapeutic effects on stress-related disorders. While the underlying mechanisms of therapeutic actions of psychedelic compounds are still unclear, these drugs are thought to modulate the activity of the serotonergic system, primarily through activating serotonin type 2A receptor (5-HT2AR) and studies have focused on these actions in the medial prefrontal cortex (mPFC). 25CN-NBOH, a synthetic psychedelic compound with a high binding affinity for 5-HT2ARs and anti-anxiety actions, has emerged as a valuable tool for investigating the physiological functions mediated by this receptor. This study aimed to investigate the electrophysiological effects of 25CN-NBOH on pyramidal mPFC neurons using whole-cell patch clamp recordings in mouse brain slices. We recorded synaptic events and action potential rates during acute and long-term exposure to two concentrations of 25CN-NBOH. Acute application of 10 µM 25CN-NBOH increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) that was reliant on activation of 5-HT2AR, and which was not seen upon chronic exposure. A similar effect of 200 nM 25CN-NBOH was not noted. Surprisingly, both 10 µM and 200 nM 25CN-NBOH significantly suppressed the firing rate following acute as well as a longer-term exposure of 1 h. This suppression was independent of 5-HT2AR activation but was mediated by M-current channels, as evidenced by the reversal of suppression with the M-current blocker XE-991. Our data suggest a complicated dual action of 25CN-NBOH in enhancing excitatory transmission while also reducing excitability. Our data contribute to knowledge regarding the cellular consequence of 5-HT2AR agonism and contribute to widening our understanding of the potential mechanisms underlying the therapeutic actions of serotonergic psychedelics.