The effects of serotonergic psychedelics in synaptic and intrinsic properties of neurons in layer II/III of the orbitofrontal cortex.
Psychopharmacology – June 01, 2023
Source: PubMed
Summary
Psychedelics like 25C-NBOMe can significantly alter brain activity, particularly in the orbitofrontal cortex (OFC), a region linked to compulsive behaviors. In a study with adult male Sprague Dawley rats, 25C-NBOMe enhanced spontaneous neurotransmission at glutamatergic synapses by 30% while reducing GABAergic transmission by 20%. This compound also boosted excitatory currents and action potentials in pyramidal neurons, increasing their excitability. These findings suggest that psychedelics may effectively modulate the excitation/inhibition balance in the OFC, offering insights for treating psychiatric disorders.
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.