Serotonergic mechanisms involved in antidepressant-like responses evoked by GLT-1 blockade in rat infralimbic cortex
Serotonergic mechanisms involved in antidepressant-like responses evoked by GLT-1 blockade in rat infralimbic cortex
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DOI：
10.1016/j.neuropharm.2018.06.029
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发表时间：
2018-09-01
影响因子：
4.7
通讯作者：
Castane, Anna
中科院分区：
文献类型：
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作者：
Gasull-Camos, Julia;Martinez-Torres, Sara;Castane, Anna
新型快速抗抑郁药物，如氯胺酮和深部脑刺激，通过激活AMPA受体（AMPA- r）增强内侧前额叶皮层（mPFC）区域的谷氨酸能神经传递。我们最近报道，在mPFC最腹侧的大鼠边缘下皮层（IL），通过双氢克酸（DHK）微输注局部选择性阻断胶质谷氨酸转运体-1 (GLT-1)，可立即（10分钟）引起抗抑郁样反应，其中涉及AMPA-R激活，并与5-羟色胺（5-羟色胺，5-HT）释放增加有关。考虑到mPFC和5 -羟色胺能中背核（DR）之间的相互连接，在这里，我们研究了DHK微量输注的抗抑郁样反应中涉及的5 -羟色胺能机制。首先，我们发现DHK和西酞普兰应用IL引起的抗抑郁样反应是由局部5-HT1A受体（5-HT1A- r）介导的，因为它们被先前的IL WAY100635微量输注所取消。其次，IL - DHK微量输注增加了对DR的兴奋性输入，如DR中谷氨酸和5-HT释放增加以及DR中5-HT神经元中c-Fos表达选择性增加所示，而在假定的gaba能神经元中并未发生。IL DHK微量输注后，腹侧海马5-HT释放增加也支持了这一观点。有趣的是，IL - DHK引起的抗抑郁样反应持续2小时，并可通过5-HT1A自受体减弱自抑制作用延长至24小时。相比之下，IL中S-AMPA微量输注的抗抑郁样作用是短暂的。总之，我们的研究结果进一步支持IL - DR通路和上升的5-HT通路在介导谷氨酸能机制引起的抗抑郁样反应中的突出作用。(C) 2018 Elsevier Ltd.版权所有。
Novel fast-acting antidepressant strategies, such as ketamine and deep brain stimulation, enhance glutamatergic neurotransmission in medial prefrontal cortex (mPFC) regions via AMPA receptor (AMPA-R) activation. We recently reported that the regionally-selective blockade of the glial glutamate transporter-1 (GLT-1) by dihydrokainic acid (DHK) microinfusion in rat infralimbic cortex (IL), the most ventral part of the mPFC, evoked immediate (10 min) antidepressant-like responses, which involved AMPA-R activation and were associated to increased serotonin (5-hydroxytryptamine, 5-HT) release. Given the reciprocal connectivity between the mPFC and the serotonergic dorsal raphe nucleus (DR), here we examined the serotoninergic mechanisms involved in the reported antidepressant-like responses of DHK microinfusion. First, we show that antidepressant-like responses evoked by IL application of DHK and citalopram are mediated by local 5-HT1A receptors (5-HT1A-R), since they are cancelled by previous IL WAY100635 microinfusion. Second, IL DHK microinfusion increases excitatory inputs onto DR, as shown by an increased glutamate and 5-HT release in DR and by a selective increase of c-Fos expression in DR 5-HT neurons, not occurring in putative GABAergic neurons. This view is also supported by an increased 5-HT release in ventral hippocampus following IL DHK microinfusion. Interestingly, antidepressant-like responses evoked by IL DHK lasted for 2 h and could be prolonged for up to 24 h by attenuating self-inhibitory effects via 5-HT1A autoreceptors. In contrast, the antidepressant-like effects of S-AMPA microinfusion in IL were short-lasting. Together, our results further support a prominent role of the IL DR pathway and of ascending 5-HT pathways in mediating antidepressant-like responses evoked by glutamatergic mechanisms. (C) 2018 Elsevier Ltd. All rights reserved.