Paul Ian A, Skolnick Phil
Laboratory of Neurobehavioral Pharmacology and Immunology, Division of Neurobiology and Behavior Research, Department of Psychiatry, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Ann N Y Acad Sci. 2003 Nov;1003:250-72. doi: 10.1196/annals.1300.016.
The past decade has seen a steady accumulation of evidence supporting a role for the excitatory amino acid (EAA) neurotransmitter, glutamate, and its receptors in depression and antidepressant activity. To date, evidence has emerged indicating that N-methyl-d-aspartate (NMDA) receptor antagonists, group I metabotropic glutamate receptor (mGluR1 and mGluR5) antagonists, as well as positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have antidepressant-like activity in a variety of preclinical models. Moreover, antidepressant-like activity can be produced not only by drugs modulating the glutamatergic synapse, but also by agents that affect subcellular signaling systems linked to EAA receptors (e.g., nitric oxide synthase). In view of the extensive colocalization of EAA and monoamine markers in nuclei such as the locus coeruleus and dorsal raphe, it is likely that an intimate relationship exists between regulation of monoaminergic and EAA neurotransmission and antidepressant effects. Further, there is also evidence implicating disturbances in glutamate metabolism, NMDA, and mGluR1,5 receptors in depression and suicidality. Finally, recent data indicate that a single intravenous dose of an NMDA receptor antagonist is sufficient to produce sustained relief from depressive symptoms. Taken together with the proposed role of neurotrophic factors in the neuroplastic responses to stressors and antidepressant treatments, these findings represent exciting and novel avenues to both understand depressive symptomatology and develop more effective antidepressants.
在过去十年中，越来越多的证据支持兴奋性氨基酸（EAA）神经递质谷氨酸及其受体在抑郁症和抗抑郁活性中发挥作用。迄今为止，已有证据表明，N-甲基-D-天冬氨酸（NMDA）受体拮抗剂、I组代谢型谷氨酸受体（mGluR1和mGluR5）拮抗剂以及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的正向调节剂在多种临床前模型中具有抗抑郁样活性。此外，不仅调节谷氨酸能突触的药物，而且影响与EAA受体相关的亚细胞信号系统的药物（如一氧化氮合酶）都能产生抗抑郁样活性。鉴于EAA和单胺标记物在蓝斑和中缝背核等核团中广泛共定位，单胺能和EAA神经传递的调节与抗抑郁作用之间可能存在密切关系。此外，也有证据表明谷氨酸代谢、NMDA和mGluR1、5受体的紊乱与抑郁症和自杀行为有关。最后，最近的数据表明，单次静脉注射NMDA受体拮抗剂足以持续缓解抑郁症状。结合神经营养因子在对应激源和抗抑郁治疗的神经可塑性反应中的作用，这些发现为理解抑郁症状学和开发更有效的抗抑郁药物提供了令人兴奋的新途径。
