Antipsychotic-induced gene regulation in multiple brain regions.
The molecular mechanism of action of antipsychotic drugs is not well understood. Their complex receptor affinity profiles indicate that their action could extend beyond dopamine receptor blockade. Single gene expression studies and high-throughput gene profiling have shown the induction of genes from several molecular classes and functional categories. Using a focused microarray approach, we investigated gene regulation in rat striatum, frontal cortex, and hippocampus after chronic administration of haloperidol or olanzapine. Regulated genes were validated by in situ hybridization, real-time PCR, and immunohistochemistry. Only limited overlap was observed in genes regulated by haloperidol and olanzapine. Both drugs elicited maximal gene regulation in the striatum and least in the hippocampus. Striatal gene induction by haloperidol was predominantly in neurotransmitter signaling, G-protein coupled receptors, and transcription factors. Olanzapine prominently induced retinoic acid and trophic factor signaling genes in the frontal cortex. The data also revealed the induction of several genes that could be targeted in future drug development efforts. The study uncovered the induction of several novel genes, including somatostatin receptors and metabotropic glutamate receptors. The results demonstrating the regulation of multiple receptors and transcription factors suggests that both typical and atypical antipsychotics could possess a complex molecular mechanism of action.
Girgenti
Matthew James
MJ
Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Nisenbaum
Laura K
LK
Bymaster
Franklin
F
Terwilliger
Rosemarie
R
Duman
Ronald S
RS
Newton
Samuel Sathyanesan
SS
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism; D000077152:Olanzapine; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D014150:Antipsychotic Agents; D018377:Neurotransmitter Agents; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D001569:Benzodiazepines; C033563:haloperidol decanoate; D006220:Haloperidol; D000077152:Olanzapine