Dynamic regulation of glutamatergic postsynaptic activity in rat prefrontal cortex by repeated administration of antipsychotic drugs
Dynamic regulation of glutamatergic postsynaptic activity in rat prefrontal cortex by repeated administration of antipsychotic drugs
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DOI：
10.1124/mol.107.043786
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发表时间：
2008-05-01
影响因子：
3.6
通讯作者：
Riva, Marco Andrea
中科院分区：
文献类型：
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作者：
Fumagalli, Fabio;Frasca, Angelisa;Riva, Marco Andrea
抗精神病药物是治疗精神分裂症的主要药物。虽然这些药物作用于几种神经递质受体，但预计它们会在与精神分裂症相关的结构上引起不同的神经适应性变化。由于多巴胺能功能障碍在精神分裂症的病理生理学中起着重要作用，我们将重点放在抗精神病药物重复治疗后的多巴胺能神经传递上。将大鼠暴露于第一代抗精神病药物氟哌啶醇和第二代抗精神病药物奥氮平的2周药物治疗。采用免疫印迹和免疫沉淀技术，研究了大鼠前额叶皮层神经元突触主要成分的表达、运输和相互作用。氟哌啶醇（而非奥氮平）长期治疗可通过选择性降低强制性N-甲基-D-天冬氨酸（NMDA）亚基NR 1、调节性NMDA亚基NR 2A及其支架蛋白突触后密度95的突触水平以及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）谷氨酸受体亚基1向膜的转运，动态影响谷氨酸能突触。此外，氟哌啶醇改变突触部位II型钙调蛋白激酶的总水平和磷酸化水平及其与调节性NMDA亚基NR 2B的相互作用。我们的数据表明，多巴胺能突触是一个脆弱的目标，长期氟哌啶醇治疗。前额叶皮层的海马体功能的整体衰减可能至少部分解释了氟哌啶醇治疗患者中观察到的认知恶化。
Antipsychotics are the mainstay for the treatment of schizophrenia. Although these drugs act at several neurotransmitter receptors, they are expected to elicit different neuroadaptive changes at structures relevant for schizophrenia. Because glutamatergic dysfunction plays a role in the pathophysiology of schizophrenia, we focused our analysis on glutamatergic neurotransmission after repeated treatment with antipsychotic drugs. Rats were exposed to a 2-week pharmacological treatment with the first generation antipsychotic haloperidol and the second generation antipsychotic olanzapine. By using Western blot and immunoprecipitation techniques, we investigated the expression, trafficking, and interaction of essential components of glutamatergic synapse in rat prefrontal cortex. Prolonged treatment with haloperidol, but not olanzapine, dynamically affects glutamatergic synapse by selectively reducing the synaptic level of the obligatory N-methyl-D-aspartate (NMDA) subunit NR1, the regulatory NMDA subunit NR2A, and its scaffolding protein postsynaptic density 95 as well as the trafficking of subunit 1 of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor to the membrane. In addition, haloperidol alters total as well as phosphorylated levels of calcium calmodulin kinase type II at synaptic sites and its interaction with the regulatory NMDA subunit NR2B. Our data suggest that the glutamatergic synapse is a vulnerable target for prolonged haloperidol treatment. The global attenuation of glutamatergic function in prefrontal cortex might explain, at least in part, the cognitive deterioration observed in patients treated with haloperidol.