title: Effect of antipsychotic drugs on gene expression in the prefrontal cortex and nucleus accumbens in the spontaneously hypertensive rat (SHR).
abstract: 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.
authors.affiliation: 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.
authors.forename: Marcos Leite
authors.initials: ML
authors.lastname: Santoro
authors.affiliation: 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.
authors.forename: Vanessa Kiyomi
authors.initials: VK
authors.lastname: Ota
authors.affiliation: Department of Biophysics and Investigation Center for Gene Therapy, Universidade Federal de Sao Paulo (UNIFESP), Rua Mirassol 207, CEP:04044-010, Brazil.
authors.forename: Roberta Sessa
authors.initials: RS
authors.lastname: Stilhano
authors.affiliation: 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.
authors.forename: Patrícia Natália
authors.initials: PN
authors.lastname: Silva
authors.affiliation: 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 Pharmacology, Universidade Federal de Sao Paulo (UNIFESP), Rua Pedro de Toledo 669, 5th floor, CEP: 04039032, Brazil.
authors.forename: Camila Maurício
authors.initials: CM
authors.lastname: Santos
authors.affiliation: 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 Pharmacology, Universidade Federal de Sao Paulo (UNIFESP), Rua Pedro de Toledo 669, 5th floor, CEP: 04039032, Brazil.
authors.forename: Mariana Cepollaro
authors.initials: MC
authors.lastname: Diana
authors.affiliation: LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil.
authors.forename: Ary
authors.initials: A
authors.lastname: Gadelha
authors.affiliation: LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil.
authors.forename: Rodrigo Affonseca
authors.initials: RA
authors.lastname: Bressan
authors.affiliation: 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.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Melaragno
authors.affiliation: Department of Biophysics and Investigation Center for Gene Therapy, Universidade Federal de Sao Paulo (UNIFESP), Rua Mirassol 207, CEP:04044-010, Brazil.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Han
authors.affiliation: 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 Pharmacology, Universidade Federal de Sao Paulo (UNIFESP), Rua Pedro de Toledo 669, 5th floor, CEP: 04039032, Brazil.
authors.forename: Vanessa Costhek
authors.initials: VC
authors.lastname: Abílio
authors.affiliation: 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. Electronic address: sinbelangero@gmail.com.
authors.forename: Sintia Iole
authors.initials: SI
authors.lastname: Belangero
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011918:Rats, Inbred SHR; D018967:Risperidone / Q000494:pharmacology; D012559:Schizophrenia
chemical_list: D014150:Antipsychotic Agents; D018377:Neurotransmitter Agents; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone
keywords: Antipsychotic; Brs3; DNA methylation; Drd2; Drd3; Gabrr1; Galr3; Gene expression; Glra1; Spontaneously hypertensive rats