A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons.
A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons.
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DOI：
10.1016/j.biopsych.2014.07.033
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发表时间：
2015-02-15
影响因子：
10.6
通讯作者：
Kieffer BL
中科院分区：
文献类型：
--
作者：
Chu Sin Chung P;Keyworth HL;Martin-Garcia E;Charbogne P;Darcq E;Bailey A;Filliol D;Matifas A;Scherrer G;Ouagazzal AM;Gaveriaux-Ruff C;Befort K;Maldonado R;Kitchen I;Kieffer BL
阿片受体(DOR)广泛表达于神经系统，调节慢性疼痛、情绪反应、动机和记忆。DOR活动背后的神经回路一直没有被遗传学方法研究得很好。在这里，我们使用小鼠条件突变来阐明前脑GABA能神经元的受体功能。我们研究了Dlx5/6-CreXOprd1fl/fl(DLX-DOR)小鼠脑内DOR的分布，并通过行为学测试测试了DOR的主要中枢功能。在嗅球和纹状体中，DORS蛋白被强烈删除，而在皮质和杏仁基底外侧核中保持不变。嗅觉、昼夜活动和类似绝望的行为没有变化。相反，DOR激动剂SNC80和D1激动剂SKF81297的运动刺激效应分别被取消和增强。此外，DLX-DOR小鼠在升高的正迷宫中表现出较低的焦虑水平，与已知的结构性DOR基因敲除动物的高度焦虑相反。此外，DLX-DOR小鼠在新奇抑制进食(NSF)任务中获得食物的速度更快，尽管在操作型范式中观察到它们对食物奖励的动机较低。最后，NSF后杏仁核c-fos染色明显减少，这与DLX-DOR小鼠的低焦虑表型一致。在这里，我们证明了在前脑中表达的DORS介导了SNC80所描述的运动效应，并抑制了D1刺激的多动。我们的数据还揭示了这一特定DOR亚群的一个意想不到的焦虑作用，具有潜在的新的适应作用。因此，DORS在情绪反应中发挥着双重的抗焦虑/致焦虑作用，这两种作用都可能在焦虑症领域产生影响。
The delta opioid receptor (DOR) is broadly expressed throughout the nervous system and regulates chronic pain, emotional responses, motivation and memory. Neural circuits underlying DOR activities have been poorly explored by genetic approaches. Here we used conditional mouse mutagenesis to elucidate receptor function in GABAergic neurons of the forebrain. We characterized DOR distribution in the brain of Dlx5/6-CreXOprd1fl/fl (Dlx-DOR) mice, and tested main central DOR functions through behavioral testing. DORs proteins were strongly deleted in olfactory bulb and striatum, and remained intact in cortex and basolateral amygdala. Olfactory perception, circadian activity and despair-like behaviors were unchanged. In contrast, locomotor stimulant effects of SNC80 (DOR agonist) and SKF81297 (D1 agonist) were abolished and increased, respectively. Furthermore, Dlx-DOR mice showed lower levels of anxiety in the elevated plus-maze, opposing the known high anxiety in constitutive DOR knockout animals. Also Dlx-DOR mice reached the food more rapidly in a novelty suppressed feeding (NSF) task, despite their lower motivation for food reward observed in an operant paradigm. Finally, c-fos staining after NSF was strongly reduced in amygdala, concordant with the low anxiety phenotype of Dlx-DOR mice. Here we demonstrate that DORs expressed in the forebrain mediate the described locomotor effect of SNC80 and inhibit D1-stimulated hyperactivity. Our data also reveal an unanticipated anxiogenic role for this particular DOR subpopulation, with a potential novel adaptive role. DORs therefore exert dual anxiolytic/anxiogenic roles in emotional responses, which may both have implications in the area of anxiety disorders.
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影响因子：
1.6
作者：
Gavériaux-Ruff C;Kieffer BL
通讯作者：
Kieffer BL
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作者：
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Davidson, RJ
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通讯作者：
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