Activation of metabotropic glutamate (mGlu)2 receptors suppresses histamine release in limbic brain regions following acute ketamine challenge
Activation of metabotropic glutamate (mGlu)2 receptors suppresses histamine release in limbic brain regions following acute ketamine challenge
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DOI：
10.1016/j.neuropharm.2009.11.014
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发表时间：
2010-03-01
影响因子：
4.7
通讯作者：
Svensson, Kjell A.
中科院分区：
文献类型：
--
作者：
Fell, Matthew J.;Katner, Jason S.;Svensson, Kjell A.
在本研究中，我们证明氯胺酮（一种 NMDA 拮抗剂和可能的拟精神病药）会增加大鼠大脑中的细胞外组胺 (HA)。然后，我们检查了 11 族 mGlu 受体激动剂 LY379268 调节氯胺酮引起的三个边缘脑区域 HA 释放增加的能力。氯胺酮 (25 mg/kg) 增加内侧前额皮质 (mPFC)、腹侧海马 (vHipp) 和伏隔核 (NAc) 壳中的 HA。单独施用 LY379268 对 mPFC 或 vHipp 中的基础 HA 流出没有影响，但适度降低 NAc 壳中的 HA 流出。在氯胺酮之前给予 LY379268（3 和 10 mg/kg）可显着减弱 mPFC、vHipp 和 NAc 壳中的 HA 反应。 LY379268 在 mPFC 中的抑制作用通过全身给予 mGlu2 受体正变构调节剂 CBiPES (60 mg/kg) 来模拟。最后，局部灌注实验表明，LY379268 对氯胺酮引起的 HA 流出的影响似乎是由 PFC 外部的 mGlu2 受体介导的，因为 LY379268 的 mPFC 内灌注（100 μM 或 300 μM）未能减弱氯胺酮引起的 HA 流出的增加。总之，这些新的观察结果揭示了氯胺酮对边缘脑区域组胺能传递的影响，并进一步深入了解 mGlu2/3 受体激动剂可能的抗精神病作用机制。 (C) 2009 Elsevier Ltd. 保留所有权利。
In the present study we demonstrated that ketamine, an NMDA antagonist and possible psychotomimetic, increases extracellular histamine (HA) in the rat brain. We then examined the ability of the group 11 mGlu receptor agonist LY379268 to modulate the ketamine evoked increases in HA release in three limbic brain regions. Ketamine (25 mg/kg) increased HA in the medial prefrontal cortex (mPFC), ventral hippocampus (vHipp) and the nucleus accumbens (NAc) shell. LY379268 administered alone was without effect on basal HA efflux in the mPFC or vHipp but modestly decreased HA efflux in the NAc shell. Administration of LY379268 (3 and 10 mg/kg) prior to ketamine significantly attenuated the HA response in the mPFC, vHipp and the NAc shell. The inhibitory effects of LY379268 in the mPFC were mimicked by the systemic administration of the mGlu2 receptor positive allosteric modulator CBiPES (60 mg/kg). Finally, local perfusion experiments revealed that the effects of LY379268 on ketamine evoked HA efflux appear to be mediated by mGlu2 receptors outside the PFC as the intra-mPFC perfusion of LY379268 (100 mu M or 300 mu M) failed to attenuate ketamine evoked increases in HA efflux. Together, these novel observations reveal an effect of ketamine on histaminergic transmission in limbic brain areas and provide further insight into the possible antipsychotic mechanism of action of mGlu2/3 receptor agonists. (C) 2009 Elsevier Ltd. All rights reserved.