Silk Esther, Diwan Mustansir, Rabelo Thallita, Katzman Hailey, Campos Ana Carolina P, Gouveia Flavia Venetucci, Giacobbe Peter, Lipsman Nir, Hamani Clement
Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, 2075 Bayview Av, S126, Toronto, ON, M4N3M5, Canada.
Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada.
Psychopharmacology (Berl). 2022 Dec;239(12):3875-3892. doi: 10.1007/s00213-022-06259-6. Epub 2022 Oct 25.
Deep brain stimulation (DBS) delivered to the ventromedial prefrontal cortex (vmPFC) induces antidepressant- and anxiolytic-like responses in various animal models. Electrophysiology and neurochemical studies suggest that these effects may be dependent, at least in part, on the serotonergic system. In rodents, vmPFC DBS reduces raphe cell firing and increases serotonin (5-HT) release and the expression of serotonergic receptors in different brain regions.
We examined whether the behavioural responses of chronic vmPFC DBS are mediated by 5-HT or 5-HT receptors through a series of experiments. First, we delivered stimulation to mice undergoing chronic social defeat stress (CSDS), followed by a battery of behavioural tests. Second, we measured the expression of 5-HT and 5-HT receptors in different brain regions with western blot. Finally, we conducted pharmacological experiments to mitigate the behavioural effects of DBS using the 5-HT antagonist, WAY-100635, or the 5-HT antagonist, GR-127935.
We found that chronic DBS delivered to stressed animals reduced the latency to feed in the novelty suppressed feeding test (NSF) and immobility in the forced swim test (FST). Though no significant changes were observed in receptor expression, 5-HT levels in DBS-treated animals were found to be non-significantly increased in the vmPFC, hippocampus, and nucleus accumbens and reduced in the raphe compared to non-stimulated controls. Finally, while animals given vmPFC stimulation along with WAY-100635 still presented significant responses in the NSF and FST, these were mitigated following GR-127935 administration.
The antidepressant- and anxiolytic-like effects of DBS in rodents may be partially mediated by 5-HT1 receptors.
在各种动物模型中，向腹内侧前额叶皮质（vmPFC）进行深部脑刺激（DBS）可诱发抗抑郁和抗焦虑样反应。电生理学和神经化学研究表明，这些效应可能至少部分依赖于5-羟色胺能系统。在啮齿动物中，vmPFC DBS可减少中缝核细胞放电，增加5-羟色胺（5-HT）释放以及不同脑区中5-羟色胺能受体的表达。
我们通过一系列实验研究了慢性vmPFC DBS的行为反应是否由5-HT或5-HT受体介导。首先，我们对遭受慢性社会挫败应激（CSDS）的小鼠进行刺激，随后进行一系列行为测试。其次，我们用蛋白质免疫印迹法测量不同脑区中5-HT和5-HT受体的表达。最后，我们进行药理学实验，使用5-HT拮抗剂WAY-100635或5-HT拮抗剂GR-127935减轻DBS的行为效应。
我们发现，对应激动物进行慢性DBS可缩短新奇抑制摄食试验（NSF）中的摄食潜伏期，并减少强迫游泳试验（FST）中的不动时间。虽然未观察到受体表达有显著变化，但与未刺激的对照组相比，接受DBS治疗的动物在vmPFC、海马体和伏隔核中的5-HT水平无显著升高，而在中缝核中则降低。最后，虽然同时给予vmPFC刺激和WAY-100635的动物在NSF和FST中仍表现出显著反应，但在给予GR-127935后这些反应有所减轻。
DBS在啮齿动物中的抗抑郁和抗焦虑样作用可能部分由5-HT1受体介导。
