Anxiolytic activity of the MGLU2/3 receptor agonist LY354740 on the elevated plus maze is associated with the suppression of stress-induced c-fos in the hippocampus and increases in c-Fos induction in several other stress-sensitive brain regions
Anxiolytic activity of the MGLU2/3 receptor agonist LY354740 on the elevated plus maze is associated with the suppression of stress-induced c-fos in the hippocampus and increases in c-Fos induction in several other stress-sensitive brain regions
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DOI：
10.1038/sj.npp.1300321
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发表时间：
2004-03-01
影响因子：
7.6
通讯作者：
Schoepp, DD
中科院分区：
文献类型：
--
作者：
Linden, AM;Greene, SJ;Schoepp, DD
LY354740 是 II 类代谢型谷氨酸 (mGlu) 受体、mGlu2 和 mGlu3 受体的有效和选择性激动剂，在多种焦虑动物模型中具有抗焦虑活性，包括高架十字迷宫 (EPM) 测试。在这里，我们使用 c-Fos 免疫反应性作为标记，研究了盐水和 LY354740 处理的小鼠 EPM 暴露后小鼠大脑中的神经元激活。还在笼对照（无 EPM）小鼠中研究了 LY354740 对 c-Fos 表达的影响。用LY354740（20 mg/kg，s.c.）预处理对EPM产生强烈的抗焦虑行为，LY354740给药减少了EPM诱导的海马CA3中c-Fos表达的增加，而对海马中基础c-Fos表达没有显着影响。无论动物是否暴露于 EPM，LY354740 给药均显着增加特定边缘区域的 c-Fos 表达，包括杏仁核中央核 (CeL)、外侧臂旁核、蓝斑和 Edinger-Westphal 核的外侧分裂。此外，LY354740给药本身显着增加了处理感觉信息的区域的c-Fos表达，包括丘脑的室旁核和外侧膝状核以及视束核和上丘。特别是，海马中恐惧诱发的神经元活动的抑制和药物诱导的 CeL 中神经元激活的增加先前已被认为与临床有效药物（如苯二氮卓类药物）的抗焦虑作用有关，因此可能有助于 LY354740 在动物模型和人类焦虑患者中的抗焦虑作用。
LY354740 is a potent and selective agonist for group II metabotropic glutamate (mGlu) receptors, mGlu2 and mGlu3 receptors, with anxiolytic activity in several animal models of anxiety, including the elevated plus maze (EPM) test. Here, we studied neuronal activation in mouse brain after EPM exposure in saline- and LY354740-treated mice using c-Fos immunoreactivity as a marker. The effect of LY354740 on c-Fos expression was also studied in cage control (no EPM) mice. Pretreatment with LY354740 (20 mg/kg, s.c.) produced robust anxiolytic behavior on the EPM, LY354740 administration decreased EPM-induced increases in c-Fos expression in the CA3 of the hippocampus, while having no significant effects on basal c-Fos expression in the hippocampus. LY354740 administration significantly increased c-Fos expression in specific limbic regions, including the lateral division of the central nucleus of the amygdala (CeL), lateral parabrachial nucleus, locus coeruleus, and Edinger-Westphal nucleus, whether or not animals were exposed to the EPM. Moreover, LY354740 administration per se significantly increased c-Fos expression in regions processing sensory information, including the paraventricular and lateral geniculate nucleus of the thalamus as well as the nucleus of the optic tract and superior coliiculus. In particular, the suppression of fear-evoked neuronal activity in the hippocampus and drug-induced increases in neuronal activation in the CeL have been previously linked to the anxiolytic effects of clinically effective drugs such as benzodiazepines, and thus may contribute to anxiolytic actions of LY354740 in animal models and human anxiety patients.