Flores Cecilia, Coyle Joseph T
Department of Psychiatry, Harvard Medical School and McLean Hospital, Mailman Research Center, Belmont, MA, USA.
Neuropsychopharmacology. 2003 Jul;28(7):1227-34. doi: 10.1038/sj.npp.1300129. Epub 2003 Apr 9.
Mounting evidence indicates that hypofunction of NMDA glutamate receptors causes or contributes to the full symptomatology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), an endogenous neuropeptide, blocks NMDA receptors and inhibits glutamate release by activating metabotropic mGluR3 receptors. NAAG is catabolized to glutamate and N-acetyl-aspartate by the astrocytic enzyme glutamate carboxypeptidase II (GCP II). Changes in GCP II activity may be critically linked to changes in glutamatergic neurotransmission especially at NMDA receptors. We examined whether GCP II function is altered by treatment with the noncompetitive antagonist and psychotomimetic drug phencyclidine (PCP) and with the neuroleptics haloperidol (HAL) and clozapine (CLOZ), in corticolimbic brain regions of the adult rat. Chronic exposure to PCP produced significant increases in GCP II protein expression and activity in the prefrontal cortex (PFC) and hippocampus (HIPP). This effect may be explained by a compensatory response to persistent blockade of NMDA receptors. In addition, chronic treatment with neuroleptics upregulated GCP II activity, but not protein expression, in the PFC. In contrast, GCP II activity was decreased after acute exposure to HAL or CLOZ and was not changed after acute PCP treatment. These findings provide support for a role of GCP II function in the control of glutamatergic neurotransmission and suggest that some of the therapeutic actions of neuroleptic drugs may be mediated through their effects on GCP II activity. These results demonstrate that psychotomimetic and neuroleptic drugs modulate GCP II function in brain regions that are widely involved in the neuropathology of schizophrenia.
越来越多的证据表明，N-甲基-D-天冬氨酸（NMDA）谷氨酸受体功能减退导致或促成了精神分裂症的全部症状。N-乙酰天冬氨酰谷氨酸（NAAG）是一种内源性神经肽，它通过激活代谢型谷氨酸受体3（mGluR3）受体来阻断NMDA受体并抑制谷氨酸释放。NAAG被星形胶质细胞酶谷氨酸羧肽酶II（GCP II）分解为谷氨酸和N-乙酰天冬氨酸。GCP II活性的变化可能与谷氨酸能神经传递的变化密切相关，尤其是在NMDA受体处。我们研究了在成年大鼠的皮质边缘脑区，用非竞争性拮抗剂和拟精神病药物苯环己哌啶（PCP）以及用抗精神病药物氟哌啶醇（HAL）和氯氮平（CLOZ）治疗是否会改变GCP II的功能。长期暴露于PCP会使前额叶皮质（PFC）和海马体（HIPP）中的GCP II蛋白表达和活性显著增加。这种效应可能是对NMDA受体持续阻断的一种代偿反应。此外，长期使用抗精神病药物治疗会使PFC中的GCP II活性上调，但不会使蛋白表达上调。相比之下，急性暴露于HAL或CLOZ后GCP II活性降低，急性PCP治疗后GCP II活性没有变化。这些发现支持了GCP II功能在控制谷氨酸能神经传递中的作用，并表明抗精神病药物的一些治疗作用可能是通过它们对GCP II活性的影响来介导的。这些结果表明，拟精神病药物和抗精神病药物在广泛参与精神分裂症神经病理学的脑区中调节GCP II功能。
