Chakroborty Shreaya, Geisbush Thomas R, Dale Elena, Pehrson Alan L, Sánchez Connie, West Anthony R
Department of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States.
Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, MA, United States.
Front Pharmacol. 2017 Oct 26;8:764. doi: 10.3389/fphar.2017.00764. eCollection 2017.
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-HT receptor agonism, 5-HT receptor partial agonism, and 5-HT, 5-HT, and 5-HT 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 [selective serotonin reuptake inhibitors (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.
前额叶-皮质下回路支持执行功能，而执行功能在精神疾病中常常出现功能失调。伏硫西汀是一种多模式抗抑郁药，目前在临床上用于治疗重度抑郁症。伏硫西汀的作用机制包括阻断5-羟色胺（5-HT）转运体、激动5-HT受体、部分激动5-HT受体以及拮抗5-HT、5-HT和5-HT受体。伏硫西汀可促进内侧前额叶皮质（mPFC）中的5-HT传递，然而，这种化合物对相关前额叶-皮质下回路的影响尚不清楚。因此，本研究检测了静脉注射伏硫西汀（0.8mg/kg）对氨基甲酸乙酯麻醉大鼠前扣带回皮质（ACC）、伏隔核内侧壳（msNAc）和外侧隔核（LSN）中mPFC电刺激诱发的自发放电和动作电位的影响。我们还检测了伏硫西汀是否调节了来自海马伞（HF）输入的msNAc中的传入驱动。使用选择性5-HT再摄取抑制剂[选择性5-羟色胺再摄取抑制剂（SSRI）]艾司西酞普兰（1.6mg/kg，静脉注射）进行了类似研究，以便比较伏硫西汀的多模式作用和SSRI介导的效应。各治疗组在ACC、msNAc和LSN中的自发放电活动未观察到显著差异。在ACC中未观察到治疗对mPFC诱发反应的显著影响。相比之下，与对照组和艾司西酞普兰治疗组的平行研究相比，伏硫西汀降低了msNAc中记录到的mPFC诱发活动。因此，伏硫西汀可能通过一种机制降低mPFC-msNAc传入驱动，该机制除了类似SSRI的作用外，还需要5-HT受体调节。在LSN中的记录显示，与对照组和伏硫西汀治疗组相比，艾司西酞普兰给药后mPFC诱发活动显著增加，表明伏硫西汀对5-HT受体的复杂调节可能抵消了该区域类似SSRI的作用。最后，伏硫西汀和艾司西酞普兰给药后，msNAc中的神经元对HF刺激的反应更强，表明5-HT张力升高和5-HT受体调节可能促进该区域兴奋性海马突触驱动。上述发现表明伏硫西汀具有复杂的5-HT受体依赖性效应，这可能有助于其对前额叶-皮质下回路功能的独特影响以及开发治疗情绪障碍的新策略。
