Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milano, Italy.
Neurochem Int. 2011 Aug;59(2):138-49. doi: 10.1016/j.neuint.2011.05.002. Epub 2011 Jun 13.
Stressful life events impact on memory, cognition and emotional responses, and are known to precipitate mood/anxiety disorders. It is increasingly recognized that stress and its neurochemical and endocrine mediators induce changes in glutamate synapses and circuitry, and this in turn modify mental states. Half a century after the monoamine hypothesis, it is widely accepted that maladaptive changes in excitatory/inhibitory circuitry have a primary role in the pathophysiology of mood/anxiety disorders. The neuroplasticity hypothesis posits that volumetric changes consistently found in limbic and cortical areas of depressed subjects are in good part due to remodeling of neuronal dendritic arbors and loss of synaptic spines. A considerable body of work, carried out with in vivo microdialysis as well as alternative methodologies, has shown that both stress and corticosterone treatment induce enhancement of activity-dependent glutamate release. Accordingly, results from preclinical studies suggest that stress- and glucocorticoid-induced enhancement of glutamate release and transmission plays a main role in the induction of maladaptive cellular effects, in turn responsible for dendritic remodeling. Additional recent work has showed that drugs employed for therapy of mood/anxiety disorders (antidepressants) prevent the enhancement of glutamate release induced by stress. Understanding the action of traditional drugs on glutamate transmission could be of great help in developing drugs that may work directly at this level.
生活应激事件会影响记忆、认知和情绪反应，已知其可引发情绪/焦虑障碍。越来越多的人认识到，压力及其神经化学和内分泌介质会导致谷氨酸突触和回路发生变化，进而改变精神状态。单胺假说提出半个世纪后，人们普遍认为，兴奋性/抑制性回路的适应性变化在情绪/焦虑障碍的病理生理学中起主要作用。神经可塑性假说认为，抑郁患者边缘和皮质区域一致发现的体积变化在很大程度上是由于神经元树突分支的重塑和突触棘的丢失。大量的研究工作，包括使用活体微透析以及替代方法，表明应激和皮质酮处理都会诱导活性依赖型谷氨酸释放的增强。因此，临床前研究结果表明，应激和糖皮质激素诱导的谷氨酸释放和传递增强在诱导适应性细胞效应中起主要作用，进而导致树突重塑。最近的其他研究表明，用于治疗情绪/焦虑障碍的药物（抗抑郁药）可阻止应激引起的谷氨酸释放增强。了解传统药物对谷氨酸传递的作用可能有助于开发可直接在该水平发挥作用的药物。
