Zavitsanou Katerina, Nguyen Vu, Newell Kelly, Ballantyne Patrice, Huang Xu Feng
Australian Nuclear Science and Technology Organisation (ANSTO), Sydney, NSW, Australia.
J Chem Neuroanat. 2008 Oct;36(2):71-6. doi: 10.1016/j.jchemneu.2008.06.004. Epub 2008 Jul 2.
Phencyclidine (PCP), a non-competitive NMDA/glutamate receptor antagonist, is a psychotomimetic drug that produces a syndrome in normal humans that resembles schizophrenia. The present study investigated the mechanisms of PCP actions by examining the density of glutamate and muscarinic receptors in the rat brain 4h after a single injection of PCP. We used receptor autoradiography and [3H]MK801, [3H]AMPA, [3H]pirenzepine and [3H]AFDX384 to target glutamate NMDA, glutamate AMPA and muscarinic M1 and M2 receptors, respectively. The major outcome from the present study was an overall decrease in levels of the glutamate AMPA receptor density (F=14.5, d.f.=1, p<0.001) in the PCP treated rats. More specifically, PCP-treated animals displayed decreased AMPA receptor density in hippocampus CA1 (-16%), hippocampus CA2 (-25%), dentate gyrus (-27%), parietal cortex layers III-VI (-19%), central nucleus of the amygdala (-40%), and basolateral amygdala (-19%). Other brain regions examined were unaffected. PCP administration did not significantly affect glutamate NMDA, muscarinic M1 and M2 receptor density. The present study demonstrates the limbic system as the anatomical locus of alterations in AMPA receptor density after acute administration of PCP and may have implications for models of schizophrenia that focus on glutamatergic dysfunction in limbic cortical regions.
苯环利定（PCP）是一种非竞争性N-甲基-D-天冬氨酸/谷氨酸受体拮抗剂，是一种拟精神病药物，可在正常人中产生类似精神分裂症的综合征。本研究通过检查单次注射PCP后4小时大鼠脑中谷氨酸和毒蕈碱受体的密度，来探究PCP的作用机制。我们使用受体放射自显影技术，分别用[3H]MK801、[3H]AMPA、[3H]哌仑西平和[3H]AFDX384来靶向谷氨酸N-甲基-D-天冬氨酸受体、谷氨酸α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体以及毒蕈碱M1和M2受体。本研究的主要结果是，接受PCP治疗的大鼠中谷氨酸α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体密度水平总体下降（F = 14.5，自由度= 1，p <0.001）。更具体地说，接受PCP治疗的动物在海马CA1区（-16%）、海马CA2区（-25%）、齿状回（-27%）、顶叶皮质III - VI层（-19%）、杏仁核中央核（-40%）和杏仁核基底外侧核（-19%）的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体密度降低。其他检查的脑区未受影响。给予PCP对谷氨酸N-甲基-D-天冬氨酸受体、毒蕈碱M1和M2受体密度没有显著影响。本研究表明，边缘系统是急性给予PCP后α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体密度改变的解剖学部位，可能对关注边缘皮质区域谷氨酸能功能障碍的精神分裂症模型有影响。
