Santoro Marcos Leite, Ota Vanessa Kiyomi, Stilhano Roberta Sessa, Silva Patrícia Natália, Santos Camila Maurício, Diana Mariana Cepollaro, Gadelha Ary, Bressan Rodrigo Affonseca, Melaragno Maria Isabel, Han Sang Won, Abílio Vanessa Costhek, Belangero Sintia Iole
Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitao da Cunha, 1° andar, CEP 04023-900 São Paulo, Brazil; LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil.
Department of Biophysics and Investigation Center for Gene Therapy, Universidade Federal de Sao Paulo (UNIFESP), Rua Mirassol 207, CEP:04044-010, Brazil.
Schizophr Res. 2014 Aug;157(1-3):163-8. doi: 10.1016/j.schres.2014.05.015. Epub 2014 Jun 2.
Antipsychotic drugs (APDs) are the standard treatment for schizophrenia. The therapeutic effect of these drugs is dependent upon the dopaminergic D2 blockade, but they also modulate other neurotransmitter pathways. The exact mechanisms underlying the clinical response to APDs are not fully understood. In this study, we compared three groups of animals for the expression of 84 neurotransmitter genes in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Each group was treated with a different APD (risperidone, clozapine or haloperidol), and with a non-treated group of spontaneously hypertensive rats (SHRs), which is an animal model for schizophrenia. This study also explored whether or not differential expression was regulated by DNA methylation in the promoter region (PR). In the clozapine group, we found that Chrng was downregulated in the NAcc and six genes were downregulated in the PFC. In the haloperidol group, Brs3 and Glra1 were downregulated, as was Drd2 in the clozapine group and Drd3, Galr3 and Gabrr1 in the clozapine and haloperidol groups. We also encountered four hypermethylated CG sites in the Glra1 PR, as well as three in the risperidone group and another in the haloperidol group, when compared to non-treated rats. Following the APD treatment, the gene expression results revealed the involvement of genes that had not previously been described, in addition to the activity of established genes. The investigation of the involvement of these novel genes can lead to better understanding about the specific mechanisms of action of the individual APDs studied.
抗精神病药物（APDs）是治疗精神分裂症的标准药物。这些药物的治疗效果依赖于多巴胺能D2受体阻断，但它们也会调节其他神经递质通路。APDs临床反应的具体机制尚未完全明确。在本研究中，我们比较了三组动物前额叶皮质（PFC）和伏隔核（NAcc）中84种神经递质基因的表达情况。每组分别用不同的APD（利培酮、氯氮平或氟哌啶醇）进行治疗，同时设置一组未经治疗的自发性高血压大鼠（SHRs）作为精神分裂症动物模型。本研究还探讨了启动子区域（PR）的DNA甲基化是否调节了差异表达。在氯氮平组中，我们发现Chrng在NAcc中表达下调，六个基因在PFC中表达下调。在氟哌啶醇组中，Brs3和Glra1表达下调，氯氮平组中的Drd2以及氯氮平和氟哌啶醇组中的Drd3、Galr3和Gabrr1也表达下调。与未治疗的大鼠相比，我们还在Glra1的PR中发现了四个高甲基化的CG位点，利培酮组中有三个，氟哌啶醇组中有一个。APD治疗后，基因表达结果显示，除了已确定的基因活性外，此前未被描述的基因也参与其中。对这些新基因参与情况的研究有助于更好地理解所研究的各个APD的具体作用机制。
