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

  • Psychopharmacology (Berl). 2023 Apr 18. doi: 10.1007/s00213-023-06366-y.
Zi-Hang Tang  1 ,  Zhi-Peng Yu  1  2 ,  Qiong Li  1 ,  Xiao-Qin Zhang  1 ,  Kadeliya Muhetaer  1 ,  Zheng-Chun Wang  1 ,  Peng Xu  3 ,  Hao-Wei Shen  4  5
Affiliations
  • 1. Department of Physiology and Pharmacology, School of Medicine, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, People's Republic of China.
  • 2. Faculty of Electrical Engineering and Computer Science, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, People's Republic of China.
  • 3. Key Laboratory of Drug Monitoring and Control, Drug Intelligence and Forensic Center, Ministry of Public Security, Beijing, 100093, People's Republic of China.
  • 4. Department of Physiology and Pharmacology, School of Medicine, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, People's Republic of China. [email protected].
  • 5. Key Laboratory of Addiction Research of Zhejiang Province, Ningbo Kangning Hospital, Ningbo, Zhejiang, 315010, People's Republic of China. [email protected].
PMID: 37071130 DOI: 10.1007/s00213-023-06366-y
Abstract

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-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.

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.

Keywords
5-HT2A receptor; Excitation/inhibition balance; Orbitofrontal cortex; Psychedelics.
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