Holmes Andrew, Kinney Jefferson W, Wrenn Craige C, Li Qian, Yang Rebecca J, Ma Li, Vishwanath Janani, Saavedra Maria C, Innerfield Caitlin E, Jacoby Arie S, Shine John, Iismaa Tiina P, Crawley Jacqueline N
Section on Behavioral Genomics, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA.
Neuropsychopharmacology. 2003 Jun;28(6):1031-44. doi: 10.1038/sj.npp.1300164. Epub 2003 Apr 9.
The neuropeptide galanin coexists with norepinephrine and serotonin in neural systems mediating emotion. Previous findings suggested that galanin modulates anxiety-related behaviors in rodents. Three galanin receptor subtypes have been cloned; however, understanding their functions has been limited by the lack of galanin receptor subtype-selective ligands. To study the role of the galanin GAL-R1 receptor subtype in mediating anxiety-related behavior, we generated mice with a null mutation in the Galr1 gene. GAL-R1 -/- are viable and show no abnormalities in health, neurological reflexes, motoric functions, or sensory abilities. On a battery of tests for anxiety-like behavior, GAL-R1 -/- showed increased anxiety-like behavior on the elevated plus-maze test. Anxiety-related behaviors on the light/dark exploration, emergence, and open field tests were normal in GAL-R1 -/-. This test-specific anxiety-like phenotype was confirmed in a second, independent cohort of GAL-R1 null mutant mice and +/+ controls. Principal components factor analysis of behavioral scores from 279 mice suggested that anxiety-like behavior on the elevated plus-maze was qualitatively distinct from behavior on other tests in the battery. In addition, exposure to the elevated plus-maze produced a significantly greater neuroendocrine response than exposure to the light/dark exploration test, as analyzed in normal C57BL/6J mice. These behavioral findings in the first galanin receptor null mutant mouse are consistent with the hypothesis that galanin exerts anxiolytic actions via the GAL-R1 receptor under conditions of relatively high stress.
神经肽甘丙肽与去甲肾上腺素和5-羟色胺在介导情绪的神经系统中共存。先前的研究结果表明，甘丙肽可调节啮齿动物的焦虑相关行为。已克隆出三种甘丙肽受体亚型；然而，由于缺乏甘丙肽受体亚型选择性配体，对它们功能的了解有限。为了研究甘丙肽GAL-R1受体亚型在介导焦虑相关行为中的作用，我们构建了Galr1基因无效突变的小鼠。GAL-R1 -/-小鼠能够存活，在健康、神经反射、运动功能或感觉能力方面均无异常。在一系列焦虑样行为测试中，GAL-R1 -/-小鼠在高架十字迷宫测试中表现出焦虑样行为增加。在明暗探索、出现和旷场测试中的焦虑相关行为在GAL-R1 -/-小鼠中是正常的。在第二批独立的GAL-R1无效突变小鼠和+/+对照小鼠中证实了这种测试特异性的焦虑样表型。对279只小鼠行为评分的主成分因子分析表明，高架十字迷宫上的焦虑样行为在性质上与该系列中其他测试的行为不同。此外，正如在正常C57BL/6J小鼠中分析的那样，暴露于高架十字迷宫比暴露于明暗探索测试产生了明显更大的神经内分泌反应。第一只甘丙肽受体无效突变小鼠的这些行为学发现与以下假设一致：在相对高应激条件下，甘丙肽通过GAL-R1受体发挥抗焦虑作用。
