Polese Daniela, de Serpis Antonella Amato, Ambesi-Impiombato Alberto, Muscettola Giovanni, de Bartolomeis Andrea
Department of Neuroscience and Behavioral Sciences, Laboratory of Molecular Psychiatry and Psychopharmacotherapy, Section of Psychiatry, University School of Medicine Federico II, Naples, Italy.
Neuropsychopharmacology. 2002 Dec;27(6):906-13. doi: 10.1016/S0893-133X(02)00371-8.
N-methyl-D-aspartate receptor hypofunction has been suggested to play a role in the pathophysiology of schizophrenia. New glutamatergic mechanisms involving metabotropic receptors have been recently proposed to further expand this hypothesis. "Homer" is a family of postsynaptic density proteins functionally and physically attached to glutamate metabotropic receptors. We investigated the activation of the early gene form of Homer after acute treatment with typical or atypical antipsychotic drugs alone or with the adjunction of D-cycloserine. This activation was compared with that of c-fos, considered a putative molecular marker of brain regions activated by antipsychotics. Male Sprague-Dawley rats were treated intraperitoneally with haloperidol (0.8 mg/Kg) or clozapine (15 mg/Kg) alone or with the adjunction of D-cycloserine (20 mg/Kg). Rats were sacrificed ninety minutes after injection and the brains were processed for quantitative in situ hybridization histochemistry. Haloperidol induced a statistically significant increase of Homer both in caudate-putamen and nucleus accumbens compared with controls; clozapine induced Homer significantly only in the accumbens. The adjunction of D-cycloserine attenuated the haloperidol-induced increase of Homer expression in caudate-putamen and nucleus accumbens and attenuated the clozapine-induced increase in the accumbens. The c-fos gene expression was potently induced by haloperidol in caudate-putamen and nucleus accumbens, and by clozapine only in the accumbens. The adjunction of D-cycloserine enhanced c-fos expression only for clozapine in both regions of the forebrain. These results demonstrate a differential involvement of glutamatergic metabotropic system in gene expression modulation induced by typical or atypical antipsychotic drugs and may suggest new molecular basis for the augmentation strategy by a glycine site partial agonist.
N-甲基-D-天冬氨酸受体功能减退被认为在精神分裂症的病理生理学中起作用。最近有人提出涉及代谢型受体的新的谷氨酸能机制来进一步拓展这一假说。“荷马蛋白（Homer）”是一类与谷氨酸代谢型受体在功能和物理上相连的突触后致密蛋白家族。我们研究了单独使用典型或非典型抗精神病药物或联合D-环丝氨酸急性治疗后荷马蛋白早期基因形式的激活情况。将这种激活与c-fos的激活进行比较，c-fos被认为是抗精神病药物激活的脑区的一种假定分子标记物。雄性Sprague-Dawley大鼠腹腔注射氟哌啶醇（0.8毫克/千克）或氯氮平（15毫克/千克），单独使用或联合D-环丝氨酸（20毫克/千克）。注射后90分钟处死大鼠，对大脑进行定量原位杂交组织化学处理。与对照组相比，氟哌啶醇使尾状核-壳核和伏隔核中的荷马蛋白有统计学意义的显著增加；氯氮平仅使伏隔核中的荷马蛋白显著增加。D-环丝氨酸的加入减弱了氟哌啶醇诱导的尾状核-壳核和伏隔核中荷马蛋白表达的增加，以及氯氮平诱导的伏隔核中荷马蛋白表达的增加。氟哌啶醇在尾状核-壳核和伏隔核中强力诱导c-fos基因表达，氯氮平仅在伏隔核中诱导c-fos基因表达。D-环丝氨酸的加入仅增强了氯氮平在前脑两个区域诱导的c-fos表达。这些结果表明谷氨酸能代谢型系统在典型或非典型抗精神病药物诱导基因表达调节中的不同参与情况，并可能为甘氨酸位点部分激动剂的增效策略提示新的分子基础。
