Clozapine and haloperidol produce a differential pattern of immediate early gene expression in rat caudate-putamen, nucleus accumbens, lateral septum and islands of Calleja.
Acute administration of the typical neuroleptic haloperidol (HAL, 2 mg/kg) induced the immediate-early gene proteins (IEGPs) c-Fos, Fos-related antigens (FRAs), FosB, JunB, JunD and Krox24 in the striatum and nucleus accumbens of the rat brain. In contrast, acute administration of the atypical antipsychotic drug clozapine (CLOZ, 30 mg/kg) induced only FRAs, JunB and Krox24 IEGPs in the striatum, and c-Fos, FRAs, and Krox24 IEGPs in the nucleus accumbens. c-Jun was not induced by acute administration of HAL or CLOZ in the rat brain. Differential induction of IEGs by HAL and CLOZ was also observed in the lateral septal nucleus and the islands of Calleja complex of the rat brain. These differences in IEG induction by HAL and CLOZ may be related to the different clinical profiles of the two drugs. Specifically, CLOZ induces FRAs in the islands of Calleja and lateral septum and this action may be involved in its therapeutic effects on the negative symptoms of schizophrenia, whereas HAL produces a coordinate induction of Fos and JunB in striatal neurons and this dimer combination may be involved in producing the extrapyramidal side-effects of typical neuroleptics.
Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, New Zealand.
G A
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MacGibbon
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PA
Lawlor
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Bravo
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Dragunow
D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004409:Dyskinesia, Drug-Induced / Q000209:etiology; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation / Q000187:drug effects*; D017781:Genes, Immediate-Early; D006220:Haloperidol / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D009833:Olfactory Pathways / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012688:Septum Pellucidum / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D003024:Clozapine; D006220:Haloperidol