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.
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Data availability
The datasets generated or analyzed during this study are available from the corresponding author on reasonable request.
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Acknowledgements
The project was funded by the National Key Research and Development Program of China (2022YFC3300905) and the Natural Science Foundation of China (grant numbers 32171017 and 31,571,094) to H-W S.
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H-W S and Z-H T were responsible for the overall experimental design and the drafting of the manuscript. Z-H T, X-Q Z, and Z–C W contributed to the acquisition of electrophysiology data. Z-P Y, Q L, and K M assisted with data analysis and interpretation. P X helped with the experimental design. All of the authors critically reviewed the content and approved the final version of the manuscript for publication.
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Tang, ZH., Yu, ZP., Li, Q. et al. The effects of serotonergic psychedelics in synaptic and intrinsic properties of neurons in layer II/III of the orbitofrontal cortex. Psychopharmacology 240, 1275–1285 (2023). https://doi.org/10.1007/s00213-023-06366-y
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DOI: https://doi.org/10.1007/s00213-023-06366-y