Comparative gene expression study of the chronic exposure to clozapine and haloperidol in rat frontal cortex. 2012

S Hossein Fatemi, and Timothy D Folsom, and Teri J Reutiman, and Jessica Novak, and Rachelanne H Engel
Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St. SE, MMC 392, Minneapolis, MN 55455, United States. fatem002@umn.edu

Antipsychotic drugs (APDs) are effective in treating some of the positive and negative symptoms of schizophrenia. APDs take time to achieve a therapeutic effect which suggests that changes in gene expression are involved in their efficacy. We hypothesized that there would be altered expression of specific genes associated with the etiology or treatment of schizophrenia in frontal cortex of rats that received chronic treatment with a typical APD (haloperidol) vs. an atypical APD (clozapine). Rats were administered clozapine, haloperidol, or sterile saline intraperitoneally daily for 21days. Frontal cortices from clozapine-, haloperidol-, and saline-treated rats were dissected and subjected to microarray analysis. We observed a significant (1.5 fold, p<0.05) downregulation of 278 genes and upregulation of 73 genes in the clozapine-treated brains vs. controls and downregulation of 451 genes and upregulation of 115 genes in the haloperidol-treated brains vs. control. A total of 146 genes (130 downregulated and 16 upregulated) were significantly altered by both clozapine and haloperidol. These genes were classified by functional groups. qRT-PCR (quantitative real-time polymerase chain reaction) analysis verified the direction and magnitude of change for a group of nine genes significantly altered by clozapine and 11 genes significantly altered by haloperidol. Three genes verified by qRT-PCR were altered by both drugs: Bcl2-like 1 (Bcl2l1), catechol-O-methyltransferase (Comt), and opioid-binding protein/cell adhesion molecule-like (Opcml). Our results show that clozapine and haloperidol cause changes in levels of many important genes that may be involved in etiology and treatment of schizophrenia.

UI MeSH Term Description Entries
D008297 Male Males
D011897 Random Allocation A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. Randomization,Allocation, Random
D002394 Catechol O-Methyltransferase Enzyme that catalyzes the movement of a methyl group from S-adenosylmethionone to a catechol or a catecholamine. Catechol Methyltransferase,Catechol-O-Methyltransferase,Catechol O Methyltransferase,Methyltransferase, Catechol,O-Methyltransferase, Catechol
D003024 Clozapine A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent. Clozaril,Leponex
D005625 Frontal Lobe The part of the cerebral hemisphere anterior to the central sulcus, and anterior and superior to the lateral sulcus. Brodmann Area 8,Brodmann's Area 8,Frontal Cortex,Frontal Eye Fields,Lobus Frontalis,Supplementary Eye Field,Area 8, Brodmann,Area 8, Brodmann's,Brodmanns Area 8,Cortex, Frontal,Eye Field, Frontal,Eye Field, Supplementary,Eye Fields, Frontal,Frontal Cortices,Frontal Eye Field,Frontal Lobes,Lobe, Frontal,Supplementary Eye Fields
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006220 Haloperidol A phenyl-piperidinyl-butyrophenone that is used primarily to treat SCHIZOPHRENIA and other PSYCHOSES. It is also used in schizoaffective disorder, DELUSIONAL DISORDERS, ballism, and TOURETTE SYNDROME (a drug of choice) and occasionally as adjunctive therapy in INTELLECTUAL DISABILITY and the chorea of HUNTINGTON DISEASE. It is a potent antiemetic and is used in the treatment of intractable HICCUPS. (From AMA Drug Evaluations Annual, 1994, p279) Haldol
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D014150 Antipsychotic Agents Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. Antipsychotic,Antipsychotic Agent,Antipsychotic Drug,Antipsychotic Medication,Major Tranquilizer,Neuroleptic,Neuroleptic Agent,Neuroleptic Drug,Neuroleptics,Tranquilizing Agents, Major,Antipsychotic Drugs,Antipsychotic Effect,Antipsychotic Effects,Antipsychotics,Major Tranquilizers,Neuroleptic Agents,Neuroleptic Drugs,Tranquillizing Agents, Major,Agent, Antipsychotic,Agent, Neuroleptic,Drug, Antipsychotic,Drug, Neuroleptic,Effect, Antipsychotic,Major Tranquilizing Agents,Major Tranquillizing Agents,Medication, Antipsychotic,Tranquilizer, Major

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