Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum

Noboru Hiroi, Ann M. Graybiel

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

Atypical and typical neuroleptics, when administered chronically, can bring about profound but contrasting changes in schizophrenic symptoms and motor activation and dramatically modulate brain neurochemistry. To explore the transcriptional events that might be involved in this neurochemical regulation, we used immunohistochemistry and immunoblotting to examine the expression patterns of two bZip transcription factors, c-Fos and FosB, in the striatum of rats treated acutely and chronically with neuroleptic drugs of different classes. Typical and atypical neuroleptic drugs produced contrasting regulatory effects on a FosBdike protein of ca. 36-39 kDa, the molecular weight of truncated FosB (ΔFosB). Chronic treatments with two typical neuroleptics, haloperidol and metoclopramide, but not with the atypical neuroleptic clozapine, led to markedly enhanced FosB-like immunoreactivity in the caudoputamen. Further, c-Fos-like protein in the striatum, considered a marker for the induction of antipsychotic actions by neuroleptic treatments, was downregulated by chronic treatment with the two potent antipsychotic drugs tested, but not by chronic treatment with metoclopramide, which has low antipsychotic efficacy but induces extrapyramidal side effects. These results suggest that chronic treatments with neuroleptics having different effects on cognitive and motor behavior induce different long-term changes in transcription factor expression in the striatum. Nevertheless, we found that neuroleptics of both classes regulated transcription factor expression in overlapping populations of striatal neurons expressing enkephalin or DARPP-32. Contrasting patterns of transcriptional regulation in these neurons may thus contribute to the distinct neurochemical and behavioral effects that characterize neuroleptics of different classes.

Original languageEnglish (US)
Pages (from-to)70-83
Number of pages14
JournalJournal of Comparative Neurology
Volume374
Issue number1
DOIs
StatePublished - Oct 7 1996
Externally publishedYes

Fingerprint

Antipsychotic Agents
Transcription Factors
Therapeutics
Metoclopramide
Proto-Oncogene Proteins c-fos
Neurochemistry
Neurons
Corpus Striatum
Enkephalins
Clozapine
Haloperidol
Immunoblotting
Down-Regulation
Molecular Weight
Immunohistochemistry

Keywords

  • extrapyramidal side effects
  • Fos
  • FosB
  • neuroleptics
  • striosome

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum. / Hiroi, Noboru; Graybiel, Ann M.

In: Journal of Comparative Neurology, Vol. 374, No. 1, 07.10.1996, p. 70-83.

Research output: Contribution to journalArticle

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