The effects of serotonergic psychedelics in synaptic and intrinsic properties of neurons in layer II/III of the orbitofrontal cortex.

A substituted phenethylamine psychedelic, 25C-NBOMe, increases the ratio of excitation to inhibition in the orbitofrontal cortex by enhancing glutamatergic transmission and reducing GABAergic transmission via the 5-HT2A receptor. It also boosts the intrinsic excitability of pyramidal neurons, but not fast-spiking interneurons, through mechanisms involving G protein-gated inwardly rectifying potassium channels and protein kinase C. These effects collectively shift local excitation/inhibition balance toward excitation, which may underlie the therapeutic potential of psychedelics for disorders like obsessive-compulsive disorder.

Study at a glance

Abstract

Serotonergic psychedelics show promise in the treatment of psychiatric disorders, including obsessive-compulsive disorder. Dysfunction of the orbitofrontal cortex (OFc) has been implicated in the pathophysiology of compulsive behavior, which might be a key region for the efficacy of psychedelics. However, the effects of psychedelics on the neural activities and local excitation/inhibition (E/I) balance in the OFc are unclear. This study aimed to investigate how 25C-NBOMe, a substituted phenethylamine psychedelic, regulated the synaptic and intrinsic properties of neurons in layer II/III of the OFc. Acute brain slices containing the OFc of adult male Sprague Dawley rats were used for ex vivo whole-cell recording. The synaptic and intrinsic properties of neurons were monitored using voltage and current clamps, respectively. Electrically evoked action potential (eAP) was used to measure synaptic-driven pyramidal activity. 25C-NBOMe enhanced spontaneous neurotransmission at glutamatergic synapses but diminished that in GABAergic synapses through the 5-HT2A receptor. 25C-NBOMe also increased both evoked excitatory currents and evoked action potentials. Moreover, 25C-NBOMe promoted the excitability of pyramidal neurons but not fast-spiking neurons. Either inhibiting G protein-gated inwardly rectifying potassium channels or activating protein kinase C significantly obstructed the facilitative effect of 25C-NBOMe on the intrinsic excitability of pyramidal neurons. This work reveals the multiple roles of 25C-NBOMe in modulating synaptic and neuronal function in the OFc, which collectively promotes local E/I ratios.