Doreulee N, Alania M, Mitaishvili E, Chikovani M, Chkhartishvili B
Iv. Javakhishvili Tbilisi State University, Institute of Biology, Tbilisi, Georgia.
Georgian Med News. 2009 Dec(177):59-65.
Schizophrenia is one of the most important forms of psychiatric illness and may be chronic and highly disabling. It has been suggested that specific neurochemical abnormality is due to dopaminergic overactivity in the brain. Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute Phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. Administration of PCP or ketamine in rodents has been used to model aspects of schizophrenia. Taken into consideration the role of glutamatergic system in development of schizophrenia and involvement of striatal dopaminergic receptors in generation of schizophrenia symptoms, it was planned to study functional interaction between NMDA and metabotropic glutamatergic receptors 5 (mGluR5) in schizophrenia-associated behavioral and memory disturbance and the role of mGluRs allosteric modulation in cortico-striatal synaptic plasticity. In our experiments investigation of dose-dependent effects of ketamine revealed that 0.3mg/kg ketamine induces statistical changes most of behavioral and cognitive parameters in rats. Changes in emotional state showed decrease of the number and total duration of groomings in open field experiments as wall as in passive avoidance task. Decrease of motor activity was also detected, while no significant changes were observed in number of defecations. In T-maze test it was shown that spatial memory was damaged. To determine whether mGlu5 and NMDA receptor interact to regulate complex behaviors that are relevant to cognitive disorders such as schizophrenia we focused on assessing whether the selective mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine MPEP mimics or exacerbates the effects of the NMDA receptor antagonist. Ketamine-induced memory disturbance was significantly increased after injection of mGluR5 negative allosteric modulators MPEP. In In vitro experiments the agonist at group I metabotropic glutamate receptors (mGluRI) (RS)-3,5-dihydroxyphenyl-glycine (DHPG,100 microM) evoked a persistent depression of the second component (N2) of the cortico-striatal field potential in rat slices. DHPG-induced plasticity was not NMDA-dependent. mGlu5 negative allosteric modulator MPEP diminishes the inhibition of synaptic responses induced by DHPG and completely blocked the late phase of depression. Our behavioral and in vitro data suggested that between NMDA and mGlu5 receptors there are functional interaction. Thus in some neurological or psychiatric disorders with NMDA dysfunction pharmacological manipulation of mGlu5 receptors could have therapeutic use.
精神分裂症是最重要的精神疾病形式之一，可能是慢性且极具致残性的。有人提出，特定的神经化学异常是由于大脑中多巴胺能过度活跃所致。目前认为精神分裂症与一种低谷氨酸能状态有关，急性苯环己哌啶（PCP）可模拟这种状态，PCP是N-甲基-D-天冬氨酸（NMDA）受体亚型的拮抗剂。在啮齿动物中给予PCP或氯胺酮已被用于模拟精神分裂症的某些方面。考虑到谷氨酸能系统在精神分裂症发展中的作用以及纹状体多巴胺能受体在精神分裂症症状产生中的参与，计划研究NMDA和代谢型谷氨酸能受体5（mGluR5）在精神分裂症相关行为和记忆障碍中的功能相互作用，以及mGluRs变构调节在皮质-纹状体突触可塑性中的作用。在我们的实验中，对氯胺酮剂量依赖性效应的研究表明，0.3mg/kg氯胺酮可引起大鼠大多数行为和认知参数的统计学变化。情绪状态的变化表现为旷场实验以及被动回避任务中梳理行为的次数和总持续时间减少。还检测到运动活动减少，而排便次数未观察到显著变化。在T迷宫试验中表明空间记忆受损。为了确定mGlu5和NMDA受体是否相互作用以调节与精神分裂症等认知障碍相关的复杂行为，我们着重评估选择性mGlu5受体拮抗剂2-甲基-6-（苯乙炔基）-吡啶（MPEP）是否模拟或加剧NMDA受体拮抗剂的作用。注射mGluR5负性变构调节剂MPEP后，氯胺酮诱导的记忆障碍显著增加。在体外实验中，I组代谢型谷氨酸受体（mGluRI）的激动剂（RS）-3,5-二羟基苯甘氨酸（DHPG，100μM）在大鼠脑片中诱发了皮质-纹状体场电位第二成分（N2）的持续抑制。DHPG诱导的可塑性不依赖于NMDA。mGlu5负性变构调节剂MPEP减弱了DHPG诱导的突触反应抑制，并完全阻断了抑郁的晚期阶段。我们的行为和体外数据表明，NMDA和mGlu5受体之间存在功能相互作用。因此，在一些存在NMDA功能障碍的神经或精神疾病中，对mGlu5受体进行药理学操作可能具有治疗用途。
