Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.
Neurosci Biobehav Rev. 2018 Jan;84:352-358. doi: 10.1016/j.neubiorev.2017.08.012. Epub 2017 Aug 23.
A growing body of evidence supports the idea that drugs targeting the glutamate system may represent a valuable therapeutic alternative in major depressive disorders (MDD). The rapid and prolonged mood elevating effect of the NMDA receptor (NMDAR) antagonist ketamine has been studied intensely. However, its clinical use is hampered by deleterious side-effects, such as psychosis. Therefore, a better understanding of the mechanisms of the psychotropic effects after NMDAR blockade is necessary to develop glutamatergic antidepressants with improved therapeutic profile. Here we review recent experimental data that addressed molecular/cellular determinants of the antidepressant effect mediated by inactivating NMDAR subtypes. We refer to results obtained both in pharmacological and genetic animal models, ranging from global to conditional NMDAR manipulation. Our main focus is on the contribution of different NMDAR subtypes to the psychoactive effects induced by NMDAR ablation/blockade. We review data analyzing the effect of NMDAR subtype deletions limited to specific neuronal populations/brain areas in the regulation of mood. Altogether, these studies suggest effective and putative specific NMDAR drug targets for MDD treatment.
越来越多的证据支持这样一种观点，即靶向谷氨酸系统的药物可能代表了治疗重度抑郁症（MDD）的一种有价值的治疗选择。N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂氯胺酮具有快速而持久的情绪提升作用，因此受到了深入研究。然而，其临床应用受到有害副作用的限制，例如精神病。因此，需要更好地了解 NMDAR 阻断后精神作用的机制，以便开发具有改善治疗效果的谷氨酸能抗抑郁药。在这里，我们回顾了最近的实验数据，这些数据涉及通过使 NMDAR 亚型失活介导的抗抑郁作用的分子/细胞决定因素。我们参考了在药理学和遗传动物模型中获得的结果，范围从全局到条件 NMDAR 操作。我们的主要重点是不同 NMDAR 亚型对 NMDAR 消融/阻断诱导的精神活性作用的贡献。我们回顾了分析特定神经元群体/脑区中特定 NMDAR 缺失对调节情绪的影响的数据。总之，这些研究为 MDD 治疗提供了有效的和可能的特定 NMDAR 药物靶点。
