Noga J T, Hyde T M, Herman M M, Spurney C F, Bigelow L B, Weinberger D R, Kleinman J E
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA.
Synapse. 1997 Nov;27(3):168-76. doi: 10.1002/(SICI)1098-2396(199711)27:3<168::AID-SYN2>3.0.CO;2-B.
Previous postmortem studies of glutamate receptors and uptake sites have shown decreased D-aspartate (D-Asp) (a marker for the high affinity glutamate uptake site) and elevated (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801) binding in the putamen in schizophrenia and elevated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor binding in the caudate nucleus of schizophrenics who committed suicide. The relative effects of schizophrenia, suicide, and neuroleptic treatment in these findings is unclear. This study further explores binding to glutamate receptors (NMDA, kainic acid, and AMPA) and uptake sites in postmortem striatal structures in schizophrenics relative to three control groups (normal controls, neuroleptic-treated controls, and nonpsychotic suicides).
We compared the binding densities of tritium-labeled ligands 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), kainic acid (KA), MK-801, and D-Asp, which target the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), KA, and N-methyl-D-aspartic acid (NMDA) ionotropic receptor sites and the glutamate uptake site, respectively, in postmortem striatal/accumbens tissue from six DSM-III-R schizophrenics, eight normal controls, eight neuroleptic-treated controls, and eight suicide victims using standard receptor autoradiographic methods.
Binding of [3H] CNQX (AMPA receptors) was significantly different among the four groups across the subdivisions of the striatum: caudate, putamen, and nucleus accumbens (ANOVA P = .0007, .002, and .004, respectively). The schizophrenia group had higher mean CNQX binding in the caudate nucleus than normal (P = .005) and neuroleptic controls (P = .006) but not suicides (P = .6), who were also higher than normals and neuroleptic-treated controls (P = .05). The binding densities of tritiated MK-801, KA, and D-Asp were not significantly different among the four groups of subjects in any of the striatal regions examined.
The data suggest there may be an increased density of AMPA receptor sites in the caudate nucleus in schizophrenia that is not apparently due to neuroleptic treatment. A similar increase was also seen the suicide group. Although these data do not confirm previous reports of an increase in [3H]MK-801 or a decrease in [3H]D-Asp binding in the basal ganglia in schizophrenia, the increased caudate AMPA binding observed here could reflect decreased cortical glutamatergic innervation of the caudate. Its implication for suicide is unclear.
以往对谷氨酸受体和摄取位点的尸检研究表明，在精神分裂症患者的壳核中，D-天冬氨酸（D-Asp，高亲和力谷氨酸摄取位点的标志物）减少，马来酸（+）-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺（MK-801）结合增加；而在自杀的精神分裂症患者尾状核中，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体结合增加。在这些研究结果中，精神分裂症、自杀和抗精神病药物治疗的相对影响尚不清楚。本研究进一步探讨了精神分裂症患者相对于三个对照组（正常对照组、接受抗精神病药物治疗的对照组和非精神病性自杀者）死后纹状体结构中谷氨酸受体（NMDA、 kainic 酸和 AMPA）及摄取位点的结合情况。
我们比较了氚标记配体6-氰基-7-硝基喹喔啉-2,3-二酮（CNQX）、 kainic 酸（KA）、MK-801和D-Asp的结合密度，这些配体分别靶向α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）、KA和N-甲基-D-天冬氨酸（NMDA）离子型受体位点以及谷氨酸摄取位点。我们使用标准受体放射自显影方法，对6例DSM-III-R精神分裂症患者、8例正常对照者、8例接受抗精神病药物治疗的对照者以及8例自杀受害者的死后纹状体/伏隔核组织进行了检测。
在纹状体的不同亚区（尾状核、壳核和伏隔核）中，四组之间[3H]CNQX（AMPA受体）的结合存在显著差异（方差分析，P值分别为0.0007、0.002和0.004）。精神分裂症组尾状核中CNQX的平均结合量高于正常对照组（P = 0.005）和接受抗精神病药物治疗的对照组（P = 0.006），但与自杀者组无显著差异（P = 0.6），而自杀者组的结合量也高于正常对照组和接受抗精神病药物治疗的对照组（P = 0.05）。在所检测的任何纹状体区域中，氚标记的MK-801、KA和D-Asp的结合密度在四组受试者之间均无显著差异。
数据表明，精神分裂症患者尾状核中AMPA受体位点密度可能增加，这显然不是由抗精神病药物治疗所致。自杀组也出现了类似的增加。尽管这些数据并未证实先前关于精神分裂症患者基底神经节中[3H]MK-801结合增加或[3H]D-Asp结合减少的报道，但此处观察到的尾状核AMPA结合增加可能反映了尾状核皮质谷氨酸能神经支配的减少。其对自杀的影响尚不清楚。
