University Department of Psychiatry, Warneford Hospital and Department of Neuropathology, Radcliffe Infirmary, Oxford.
J Psychopharmacol. 1994 Jan;8(4):196-203. doi: 10.1177/026988119400800402.
Glutamate receptors are implicated in several neuropsychiatric disorders and in the actions of neuroleptic drugs used to treat them. To help clarify how these drugs impinge upon the glutamatergic system, we have studied the effects of 2 weeks' haloperidol (2 mg kg(-1) d(-1)) upon the distribution and abundance of glutamate receptor mRNAs in rat brain. The mRNAs detected were those encoding the glutamate-binding protein (GBP), the N-methyl D-aspartate (NMDA) receptor (NR1 subunit) and the flip and flop isoforms of α-amino-3-hydroxy- 5-methyl-4-isoxazolpropionate (AMPA)-preferring non-NMDA receptors gluR1 and gluR2. The mRNAs were studied using in situ hybridization histochemistry in dorsolateral striatum, nucleus accumbens, frontal cortex and hippocampus. Haloperidol led to an increase in GBP mRNA in striatum and frontal cortex but not in hippocampus. AMPA receptor mRNAs showed gene- and isoform-specific alterations in treated animals, with a significant increase in the proportion of gluR2 flip compared to gluR2 flop. The gluR1 flop:gluR2 flop ratio also increased. No differences were observed for NR1 mRNA in any area. Thus, subchronic administration of haloperidol has a molecularly and spatially specific effect upon expression of glutamate receptor-related transcripts. The data have several implications. Firstly, the enhanced expression of GBP mRNA may contribute to the alterations in other glutamatergic parameters observed after neuroleptics. Secondly, the pattern of changes for the NMDA and AMPA receptor mRNAs suggests that the alterations in density of these receptors and their mRNAs reported in schizophrenia are not an artefact of neuroleptic treatment. Finally, the specific increase in flip:flop mRNA ratio for gluR2, together with the increased proportion of gluR1 flop:gluR2 flop mRNA, is likely to affect the properties of the encoded AMPA receptors. Such changes may be relevant to the desired or undesired effects of these drugs.
谷氨酸受体与多种神经精神疾病有关，也与用于治疗这些疾病的神经安定药物的作用有关。为了阐明这些药物如何影响谷氨酸能系统，我们研究了 2 周氟哌啶醇（2mgkg-1d-1）处理对大鼠脑内谷氨酸受体 mRNA 分布和丰度的影响。检测到的 mRNA 编码谷氨酸结合蛋白（GBP）、N-甲基-D-天冬氨酸（NMDA）受体（NR1 亚基）以及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）-选择性非 NMDA 受体 gluR1 和 gluR2 的翻转和翻转异构体。使用原位杂交组织化学技术在背外侧纹状体、伏隔核、额皮质和海马体中研究这些 mRNA。氟哌啶醇导致纹状体和额皮质中 GBP mRNA 增加，但海马体中没有增加。在处理后的动物中，AMPA 受体 mRNA 表现出基因和异构体特异性改变，与 gluR2 flop 相比，gluR2 flip 的比例显著增加。gluR1 flip:gluR2 flip 的比例也增加。在任何区域均未观察到 NR1 mRNA 的差异。因此，亚慢性给予氟哌啶醇对谷氨酸受体相关转录物的表达具有分子和空间特异性影响。这些数据有几个含义。首先，GBP mRNA 的增强表达可能有助于解释神经安定药后观察到的其他谷氨酸能参数的改变。其次，NMDA 和 AMPA 受体 mRNA 的变化模式表明，精神分裂症中这些受体及其 mRNA 密度的改变不是神经安定药治疗的人为因素。最后，gluR2 的 flip:flop mRNA 比率的特异性增加，以及 gluR1 flip:gluR2 flip mRNA 的比例增加，可能会影响编码的 AMPA 受体的特性。这些变化可能与这些药物的预期或非预期作用有关。
