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

• Published in: Psychopharmacology 2023-06, Vol.240 (6), p.1275-1285
• Main Authors: Tang, Zi-Hang, Yu, Zhi-Peng, Li, Qiong, Zhang, Xiao-Qin, Muhetaer, Kadeliya, Wang, Zheng-Chun, Xu, Peng, Shen, Hao-Wei
• Format: Article
• Language: English
• Subjects: Action potential; Analysis; Animals; Biomedical and Life Sciences; Biomedicine; Brain slice preparation; Complications and side effects; Excitability; Firing pattern; Glutamatergic transmission; Hallucinogenic drugs; Hallucinogens - pharmacology; Kinases; Male; Mental disorders; Neurons; Neurosciences; Neurotransmission; Original Investigation; Patient outcomes; Pharmacology/Toxicology; Phenethylamine; Potassium channels (inwardly-rectifying); Prefrontal Cortex; Protein kinase C; Psychedelic drugs; Psychiatry; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Serotonin S2 receptors; Synapses; Synaptic Transmission - physiology; γ-Aminobutyric acid
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-023-06366-y

Rationale 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. Objectives 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. Methods 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. Results 25C-NBOMe enhanced spontaneous neurotransmission at glutamatergic synapses but diminished that in GABAergic synapses through the 5-HT 2A 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. Conclusions 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.