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首页> 外文期刊>Frontiers in Neuropharmacology >Impact of Vortioxetine on Synaptic Integration in Prefrontal-Subcortical Circuits: Comparisons with Escitalopram
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Impact of Vortioxetine on Synaptic Integration in Prefrontal-Subcortical Circuits: Comparisons with Escitalopram

机译：伏替西汀对额叶-皮层下回路突触整合的影响：与艾司西酞普兰的比较。

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Prefrontal-subcortical circuits support executive functions which often become dysfunctional in psychiatric disorders. Vortioxetine is a multimodal antidepressant that is currently used in the clinic to treat major depressive disorder. Mechanisms of action of vortioxetine include serotonin (5-HT) transporter blockade, 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, and 5-HT1D, 5-HT3, and 5-HT7 receptor antagonism. Vortioxetine facilitates 5-HT transmission in the medial prefrontal cortex (mPFC), however the impact of this compound on related prefrontal-subcortical circuits is less clear. Thus, the current study examined the impact of systemic vortioxetine administration (0.8 mg/kg, i.v.) on spontaneous spiking and spikes evoked by electrical stimulation of the mPFC in the anterior cingulate cortex (ACC), medial shell of the nucleus accumbens (msNAc), and lateral septal nucleus (LSN) in urethane-anesthetized rats. We also examined whether vortioxetine modulated afferent drive in the msNAc from hippocampal fimbria (HF) inputs. Similar studies were performed using the selective 5-HT reuptake inhibitor (SSRI) escitalopram (1.6 mg/kg, i.v.) to enable comparisons between the multimodal actions of vortioxetine and SSRI-mediated effects. No significant differences in spontaneous activity were observed in the ACC, msNAc, and LSN across treatment groups. No significant impact of treatment on mPFC-evoked responses was observed in the ACC. In contrast, vortioxetine decreased mPFC-evoked activity recorded in the msNAc as compared to parallel studies in control and escitalopram treated groups. Thus, vortioxetine may reduce mPFC-msNAc afferent drive via a mechanism that, in addition to an SSRI-like effect, requires 5-HT receptor modulation. Recordings in the LSN revealed a significant increase in mPFC-evoked activity following escitalopram administration as compared to control and vortioxetine treated groups, indicating that complex modulation of 5-HT receptors by vortioxetine may offset SSRI-like effects in this region. Lastly, neurons in the msNAc were more responsive to stimulation of the HF following both vortioxetine and escitalopram administration, indicating that elevation of 5-HT tone and 5-HT receptor modulation may facilitate excitatory hippocampal synaptic drive in this region. The above findings point to complex 5-HT receptor-dependent effects of vortioxetine which may contribute to its unique impact on the function of prefrontal-subcortical circuits and the development of novel strategies for treating mood disorders.
机译：前额皮层下皮质回路支持执行功能，在精神疾病中通常会变得功能失调。伏替西汀是一种多峰抗抑郁药，目前在临床上用于治疗重度抑郁症。伏替西汀的作用机制包括5-羟色胺（5-HT）转运蛋白阻滞，5-HT1A受体激动作用，5-HT1B受体部分激动作用和5-HT1D，5-HT3和5-HT7受体拮抗作用。 Vortioxetine促进5-HT在内侧前额叶皮层（mPFC）中的传播，但是该化合物对相关的额叶前-皮层下回路的影响尚不清楚。因此，本研究检查了全身性伏立西汀给药（0.8 mg / kg，静脉注射）对前扣带回皮层（ACC），伏隔核内侧壳（msNAc）中电刺激mPFC引起的自发尖峰和尖峰的影响。和氨基甲酸乙酯麻醉大鼠的中隔外侧核（LSN）。我们还检查了海洛因纤毛（HF）输入中是否有vortioxetine调节msNAc中的传入驱动。使用选择性5-HT再摄取抑制剂（SSRI）依他普仑（1.6 mg / kg，静脉内）进行了类似的研究，以比较伏替西汀的多峰作用与SSRI介导的作用。在各治疗组中，ACC，msNAc和LSN的自发活动均无显着差异。在ACC中未观察到治疗对mPFC诱发反应的显着影响。相反，与对照组和依西酞普兰治疗组的平行研究相比，伏替西汀降低了在msNAc中记录的mPFC诱发的活性。因此，伏洛西汀可通过一种机制来减少mPFC-msNAc传入驱动，该机制除SSRI类效应外还需要调节5-HT受体。 LSN中的记录显示，与对照组和伏替西汀治疗组相比，依西酞普兰给药后mPFC诱发的活性显着增加，表明伏替西汀对5-HT受体的复杂调节可能抵消了该区域的SSRI样作用。最后，在伏替西汀和依他普仑同时给药后，msNAc中的神经元对HF的刺激反应更强，表明5-HT音调升高和5-HT受体调节可能促进该区域的兴奋性海马突触驱动。上述发现指出伏替西汀具有复杂的5-HT受体依赖性作用，这可能有助于其对前额皮层下皮质回路功能的独特影响以及治疗情绪障碍的新策略的发展。

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