Wang Yang, Kristensen Jesper L, Kohlmeier Kristi A
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Synapse. 2025 Mar;79(2):e70014. doi: 10.1002/syn.70014.
Psychedelic compounds have gained renewed interest due to their rapid and long-lasting therapeutic effects on stress-related disorders. While the underlying mechanisms of therapeutic actions of psychedelic compounds are still unclear, these drugs are thought to modulate the activity of the serotonergic system, primarily through activating serotonin type 2A receptor (5-HTR) and studies have focused on these actions in the medial prefrontal cortex (mPFC). 25CN-NBOH, a synthetic psychedelic compound with a high binding affinity for 5-HTRs and anti-anxiety actions, has emerged as a valuable tool for investigating the physiological functions mediated by this receptor. This study aimed to investigate the electrophysiological effects of 25CN-NBOH on pyramidal mPFC neurons using whole-cell patch clamp recordings in mouse brain slices. We recorded synaptic events and action potential rates during acute and long-term exposure to two concentrations of 25CN-NBOH. Acute application of 10 µM 25CN-NBOH increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) that was reliant on activation of 5-HTR, and which was not seen upon chronic exposure. A similar effect of 200 nM 25CN-NBOH was not noted. Surprisingly, both 10 µM and 200 nM 25CN-NBOH significantly suppressed the firing rate following acute as well as a longer-term exposure of 1 h. This suppression was independent of 5-HTR activation but was mediated by M-current channels, as evidenced by the reversal of suppression with the M-current blocker XE-991. Our data suggest a complicated dual action of 25CN-NBOH in enhancing excitatory transmission while also reducing excitability. Our data contribute to knowledge regarding the cellular consequence of 5-HTR agonism and contribute to widening our understanding of the potential mechanisms underlying the therapeutic actions of serotonergic psychedelics.
由于其对与压力相关的疾病具有快速且持久的治疗效果，迷幻化合物重新引起了人们的关注。虽然迷幻化合物治疗作用的潜在机制仍不清楚，但这些药物被认为主要通过激活5-羟色胺2A受体（5-HTR）来调节血清素能系统的活性，并且研究集中在这些作用于内侧前额叶皮质（mPFC）的行为上。25CN-NBOH是一种对5-HTRs具有高结合亲和力且具有抗焦虑作用的合成迷幻化合物，已成为研究该受体介导的生理功能的有价值工具。本研究旨在使用小鼠脑片的全细胞膜片钳记录来研究25CN-NBOH对mPFC锥体神经元的电生理作用。我们记录了在急性和长期暴露于两种浓度的25CN-NBOH期间的突触事件和动作电位频率。急性应用10μM 25CN-NBOH增加了依赖于5-HTR激活的自发性兴奋性突触后电流（sEPSCs）的频率，而慢性暴露时未观察到这种情况。未观察到200 nM 25CN-NBOH有类似作用。令人惊讶的是，10μM和200 nM 25CN-NBOH在急性以及1小时的长期暴露后均显著抑制放电频率。这种抑制与5-HTR激活无关，但由M电流通道介导，M电流阻滞剂XE-991使抑制作用逆转证明了这一点。我们的数据表明25CN-NBOH在增强兴奋性传递同时降低兴奋性方面具有复杂的双重作用。我们的数据有助于了解5-HTR激动作用的细胞后果，并有助于拓宽我们对血清素能迷幻药治疗作用潜在机制的理解。
