Neuroscience Development, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois [corrected] 60064-6075, USA.
Mol Pharmacol. 2010 Mar;77(3):317-26. doi: 10.1124/mol.109.059865. Epub 2009 Nov 23.
Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications that effectively treat positive symptoms of schizophrenia (e.g., delusions and hallucinations) and have been approved by regulatory agencies since the 1950s. Blockade of 5-hydroxytryptamine(2A) receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-D-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms because ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerbate the symptoms of patients with schizophrenia. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate 2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing the activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved.
多巴胺 D2 受体阻断一直是所有有效治疗精神分裂症阳性症状（如妄想和幻觉）的药物的必要作用机制，自 20 世纪 50 年代以来，这些药物已获得监管机构的批准。5-羟色胺（2A）受体的阻断在第二代抗精神病药物（所谓的非典型抗精神病药物）的作用中起辅助作用。然而，治疗阴性症状和认知功能障碍的医疗需求仍然很大。人们认识到，分离麻醉剂阻断 N-甲基-D-天冬氨酸（NMDA）受体通道，这激发了寻找谷氨酸能治疗机制的研究，因为氯胺酮和苯环利定已知会在健康志愿者中引起类似精神病的症状，并加重精神分裂症患者的症状。目前的精神分裂症病理生理学理论强调，局部回路中关键部位 NMDA 受体的功能减退调节特定脑区的功能或控制一个区域到另一个区域的投射（例如，海马-皮质或丘脑-皮质投射）。证明代谢型谷氨酸 2/3（mGlu2/3）受体激动剂前药可降低精神分裂症的阳性和阴性症状，这增加了人们的希望，即谷氨酸能机制可能提供治疗优势。除了讨论 mGlu2/3 受体激动剂或 mGlu2 受体正变构调节剂（PAMs）对 mGlu2 受体的激活外，我们还讨论了其他可能调节 NMDA 受体功能减退回路的方法，例如甘氨酸转运体抑制剂和 mGlu5 受体 PAMs。希望通过调节谷氨酸能神经传递，可以改善精神分裂症大脑的功能障碍回路（包括局部回路和长环途径）。
