Neuroscience Curriculum, School of Medicine, University of North Carolina - Chapel Hill, Chapel Hill, NC, USA; Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA.
Neuropharmacology. 2022 Apr 1;207:108943. doi: 10.1016/j.neuropharm.2022.108943. Epub 2022 Jan 7.
A stressor can trigger lasting adaptations that contribute to neuropsychiatric disorders. Predator odor (TMT) exposure is an innate stressor that may activate the metabotropic glutamate receptor 3 (mGlu) to produce stress adaptations. To evaluate functional involvement, the mGlu negative allosteric modulator (NAM, VU6010572; 3 mg/kg, i.p.) was administered before TMT exposure in male, Long Evans rats. Two weeks after, rats underwent context re-exposure, elevated zero maze (ZM), and acoustic startle (ASR) behavioral tests, followed by RT-PCR gene expression in the insular cortex and bed nucleus of the stria terminalis (BNST) to evaluate lasting behavioral and molecular adaptations from the stressor. Rats displayed stress-reactive behaviors in response to TMT exposure that were not affected by VU6010572. Freezing and hyperactivity were observed during the context re-exposure, and mGlu-NAM pretreatment during stressor prevented the context freezing response. TMT exposure did not affect ZM or ASR measures, but VU6010572 increased time spent in the open arms of the ZM and ASR habituation regardless of stressor treatment. In the insular cortex, TMT exposure increased expression of mGlu (Grm3, Grm5) and NMDA (GriN2A, GriN2B, GriN2C, GriN3A, GriN3B) receptor transcripts, and mGlu-NAM pretreatment blocked GriN3B upregulation. In the BNST, TMT exposure increased expression of GriN2B and GriN3B in vehicle-treated rats, but decreased expression in the mGlu-NAM group. Similar to the insular cortex, mGlu-NAM reversed the stressor-induced upregulation of GriN3B in the BNST. mGlu-NAM also upregulated GriN2A, GriN2B, GriN3B and Grm2 in the control group, but not the TMT group. Together, these data implicate mGlu receptor signaling in some lasting adaptations of predator odor stressor and anxiolytic-like effects.
应激源可引发持久适应，从而导致神经精神疾病。捕食者气味（TMT）暴露是一种先天应激源，可能会激活代谢型谷氨酸受体 3（mGlu）以产生应激适应。为了评估功能参与，mGlu 负变构调节剂（NAM，VU6010572；3mg/kg，ip）在雄性长耳大鼠 TMT 暴露前给予。两周后，大鼠进行了情境再暴露、高架零迷宫（ZM）和听觉惊跳（ASR）行为测试，随后对岛叶皮质和终纹床核（BNST）进行 RT-PCR 基因表达，以评估应激源的持久行为和分子适应。大鼠在 TMT 暴露后表现出应激反应行为，但 VU6010572 对其没有影响。在情境再暴露期间观察到冻结和过度活跃，而 mGlu-NAM 预处理可防止情境冻结反应。TMT 暴露不影响 ZM 或 ASR 测量，但 VU6010572 增加了 ZM 开放臂的时间和 ASR 习惯化，无论应激源处理如何。在岛叶皮质中，TMT 暴露增加了 mGlu（Grm3、Grm5）和 NMDA（GriN2A、GriN2B、GriN2C、GriN3A、GriN3B）受体转录本的表达，而 mGlu-NAM 预处理阻断了 GriN3B 的上调。在 BNST 中，TMT 暴露增加了载体处理大鼠中 GriN2B 和 GriN3B 的表达，但在 mGlu-NAM 组中减少了表达。与岛叶皮质相似，mGlu-NAM 逆转了 BNST 中应激源诱导的 GriN3B 上调。mGlu-NAM 还上调了对照组中的 GriN2A、GriN2B、GriN3B 和 Grm2，但在 TMT 组中没有上调。总之，这些数据表明，mGlu 受体信号参与了捕食者气味应激源的一些持久适应和抗焦虑样作用。
