Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex.
Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex.
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DOI：
10.3389/fnins.2014.00107
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发表时间：
2014
影响因子：
4.3
通讯作者：
Bonaventure P
中科院分区：
文献类型：
--
作者：
Aluisio L;Fraser I;Berdyyeva T;Tryputsen V;Shireman BT;Shoblock J;Lovenberg T;Dugovic C;Bonaventure P
食欲素/下丘脑泌素神经肽由下丘脑后外侧内的一簇神经元产生，并通过激活其受体（OX1和OX2受体）参与神经元调节。食欲素系统在大脑中广泛投射，并作为多个调节系统之间的接口，包括觉醒，能量平衡，压力，奖励和情绪。最近的研究表明，食欲素和谷氨酸在突触水平相互作用，食欲素促进谷氨酸的行动。我们测试的假设，食欲素调节谷氨酸信号通过OX1受体的监测水平的谷氨酸在额叶皮层的自由活动的小鼠在抑制OX1受体的条件下使用酶包被的生物传感器。皮下给予NMDA受体拮抗剂MK-801（0.178 mg/kg），以间接解除对锥体神经元的抑制，从而增加皮质谷氨酸释放。在野生型小鼠中，用OX1受体拮抗剂GSK-1059865（10 mg/kg S.C.）其本身没有作用，显著减弱MK-801引起的皮质谷氨酸释放。OX1受体敲除小鼠对MK-801的谷氨酸释放反应迟钝，表现出野生型小鼠中观察到的谷氨酸释放的约一半，与OX1受体瞬时阻断获得的数据一致。这些结果表明，药理学（瞬时）或遗传（永久）抑制OX1受体同样干扰皮质中的多巴胺能功能。用拮抗剂选择性靶向OX1受体可以使高活动状态正常化，因此可以代表用于治疗与多动状态相关的各种精神障碍的新的治疗策略。
The orexin/hypocretin neuropeptides are produced by a cluster of neurons within the lateral posterior hypothalamus and participate in neuronal regulation by activating their receptors (OX1 and OX2 receptors). The orexin system projects widely through the brain and functions as an interface between multiple regulatory systems including wakefulness, energy balance, stress, reward, and emotion. Recent studies have demonstrated that orexins and glutamate interact at the synaptic level and that orexins facilitate glutamate actions. We tested the hypothesis that orexins modulate glutamate signaling via OX1 receptors by monitoring levels of glutamate in frontal cortex of freely moving mice using enzyme coated biosensors under inhibited OX1 receptor conditions. MK-801, an NMDA receptor antagonist, was administered subcutaneously (0.178 mg/kg) to indirectly disinhibit pyramidal neurons and therefore increase cortical glutamate release. In wild-type mice, pretreatment with the OX1 receptor antagonist GSK-1059865 (10 mg/kg S.C.) which had no effect by itself, significantly attenuated the cortical glutamate release elicited by MK-801. OX1 receptor knockout mice had a blunted glutamate release response to MK-801 and exhibited about half of the glutamate release observed in wild-type mice in agreement with the data obtained with transient blockade of OX1 receptors. These results indicate that pharmacological (transient) or genetic (permanent) inhibition of the OX1 receptor similarly interfere with glutamatergic function in the cortex. Selectively targeting the OX1 receptor with an antagonist may normalize hyperglutamatergic states and thus may represent a novel therapeutic strategy for the treatment of various psychiatric disorders associated with hyperactive states.
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影响因子：
4.3
作者：
Dugovic C;Shelton JE;Yun S;Bonaventure P;Shireman BT;Lovenberg TW
通讯作者：
Lovenberg TW
影响因子：
16.2
作者：
Li, Y;Gao, XB;van den Pol, AN
通讯作者：
van den Pol, AN
影响因子：
5.3
作者：
Lee, MG;Hassani, OK;Jones, BE
通讯作者：
Jones, BE
影响因子：
3.4
作者：
Krystal, JH;D'Souza, DC;Hoffman, R
通讯作者：
Hoffman, R
影响因子：
3.7
作者：
Bonaventure P;Aluisio L;Shoblock J;Boggs JD;Fraser IC;Lord B;Lovenberg TW;Galici R
通讯作者：
Galici R