Laboratory of Translational Neuropharmacology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Int J Neuropsychopharmacol. 2013 May;16(4):919-24. doi: 10.1017/S1461145712001174. Epub 2013 Jan 29.
Anxiety and depression are highly prevalent and frequently co-morbid conditions. The ionotropic glutamate receptors N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) mediate actions of monoaminergic antidepressants and have been directly targeted by novel fast-acting antidepressants. Less is known about the role of these receptors in anxiety-like states. Here we investigate how two distinct anxiolytic agents, buspirone, a partial 5-HT(1A) agonist, and diazepam, a benzodiazepine, influence phosphorylation of GluA1 subunits of AMPA receptors at the potentiating residue Ser(845) and Ser(831) in corticolimbic regions. To test the functional relevance of these changes, phosphomutant GluA1 mice lacking phosphorylatable Ser(845) and Ser(831) were examined in relevant behavioural paradigms. These mutant mice exhibited a reduced anxiety-like phenotype in the light/dark exploration task and elevated plus maze, but not in the novelty induced hypophagia paradigm. These data indicate that reduced potentiation of the AMPA receptor signalling, via decreased GluA1 phoshorylation, is specifically involved in approach-avoidance based paradigms relevant for anxiety-like behaviours.
焦虑和抑郁是高度普遍且经常并存的疾病。离子型谷氨酸受体 N-甲基-D-天冬氨酸和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）介导单胺类抗抑郁药的作用，并且已被新型快速作用的抗抑郁药直接靶向。关于这些受体在焦虑样状态中的作用知之甚少。在这里，我们研究了两种不同的抗焦虑药物，即丁螺环酮（一种部分 5-HT1A 激动剂）和地西泮（一种苯二氮䓬），如何影响皮质边缘区域 AMPA 受体 GluA1 亚基在增强残基 Ser845 和 Ser831 处的磷酸化。为了测试这些变化的功能相关性，研究了缺乏可磷酸化 Ser845 和 Ser831 的磷酸突变型 GluA1 小鼠在相关行为范式中的表现。这些突变小鼠在明暗探索任务和高架十字迷宫中表现出焦虑样表型减少，但在新奇诱导的摄食减少范式中没有。这些数据表明，通过减少 GluA1 磷酸化，AMPAR 信号转导的增强减少，特别是与焦虑样行为相关的接近回避的基于范例相关。
