Metabotropic Glutamate Receptors: Potential Drug Targets for the Treatment of Schizophrenia
Metabotropic Glutamate Receptors: Potential Drug Targets for the Treatment of Schizophrenia
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DOI：
10.2174/1568007023339337
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发表时间：
2002-01-01
影响因子：
3
通讯作者：
Campbell, Una C.
中科院分区：
文献类型：
--
作者：
Chavez-Noriega, Laura E.;Schaffhauser, Herve;Campbell, Una C.
精神分裂症是一种使人衰弱的慢性精神疾病，影响1%的人口。精神分裂症的主要特征是阳性症状（思维障碍、幻觉、紧张性行为）、阴性症状（社交退缩、快感缺乏、冷漠）和认知障碍。虽然在阐明精神分裂症的病因进展缓慢，这种疾病的病理生理学的神经化学和神经生理学机制的新见解开始出现。精神分裂症的谷氨酸/N-甲基-D-天冬氨酸（NMDA）功能减退假说得到以下观察结果的支持：给予NMDA谷氨酸受体拮抗剂（如苯环己哌啶（PCP）或氯胺酮）可诱导人类精神病;此外，精神分裂症患者大脑中谷氨酸水平降低和谷氨酸能功能的几个标志物发生变化。给啮齿类动物施用PCP或氯胺酮可导致运动和刻板行为增加，并伴有几个脑区谷氨酸流出增加。II组代谢型谷氨酸（mGlu）受体激动剂的全身给药抑制PCP诱导的行为效应和谷氨酸外排的增加。II组mGlu受体（mGlu 2和mGlu 3）的激活减少了突触前神经末梢的谷氨酸释放，表明II组mGlu受体激动剂可能有益于治疗精神分裂症。此外，增强NMDA功能的药理学操作可能是有效的抗精神病药。mGlu 5受体的选择性激活显着增强NMDA诱导的反应，支持这种新的方法用于精神分裂症的治疗schizophrenia.The谷氨酸假说的精神分裂症的预测，代理人，恢复平衡的谷氨酸能神经传递将改善与这种疾病相关的神经病学。开发强效，有效的，全身活性药物将有助于解决这些新的therapeutics.This审查的抗精神病药物的潜力将讨论最近的进展，阐明药理学和功能的第二组mGlu和mGlu 5受体的背景下，目前的假设精神分裂症的病理生理和需要新的和更好的抗精神病药物。
Schizophrenia is a debilitating chronic psychiatric illness affecting 1% of the population. The cardinal features of schizophrenia are positive symptoms (thought disorder, hallucinations, catatonic behavior), negative symptoms (social withdrawal, anhedonia, apathy) and cognitive impairment. Although progress in elucidating the aetiology of schizophrenia has been slow, new insights on the neurochemical and neurophysiological mechanisms underlying the pathophysiology of this illness are beginning to emerge. The glutamate/N-methyl-D-aspartate (NMDA) hypofunction hypothesis of schizophrenia is supported by observations that administration of NMDA glutamate receptor antagonists such as phencyclidine (PCP) or ketamine induces psychosis in humans; moreover, decreased levels of glutamate and changes in several markers of glutamatergic function occur in schizophrenic brain. Administration of PCP or ketamine to rodents elicits an increase in locomotion and stereotypy accompanied by an increase in glutamate efflux in several brain regions. Systemic administration of group II metabotropic glutamate (mGlu) receptor agonists suppresses PCP-induced behavioral effects and the increase in glutamate efflux. Activation of group II mGlu receptors (mGlu2 and mGlu3) decreases glutamate release from presynaptic nerve terminals, suggesting that group II mGlu receptor agonists may be beneficial in the treatment of schizophrenia. In addition, pharmacological manipulations that enhance NMDA function may be efficacious antipsychotics. Selective activation of mGlu5 receptors significantly potentiates NMDA-induced responses, supporting this novel approach for the treatment of schizophrenia.The glutamate hypothesis of schizophrenia predicts that agents that restore the balance in glutamatergic neurotransmission will ameliorate the symptomatology associated with this illness. Development of potent, efficacious, systemically active drugs will help to address the antipsychotic potential of these novel therapeutics.This review will discuss recent progress in elucidating the pharmacology and function of group II mGlu and mGlu5 receptors in the context of current hypotheses on the pathophysiology of schizophrenia and the need for new and better antipsychotics.