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Distribution of Fos- and Jun-related proteins and activator protein-1 composite factors in mouse brain induced by
1Department of Neuropsychiatry, Osaka City University Medical School, Osaka, Japan.
Abstract:
The mechanisms by which the direct actions of neuroleptics are translated into therapeutic effects are unknown. We immunocytochemically investigated the expression of Fos- and Jun-related proteins and examined activator protein-1 DNA-binding activity in ddY mouse brain 120 min after the administration of haloperidol (1 mg/kg), (-)-sulpiride (20 mg/kg) and a selective dopamine D1 receptor antagonist, SCH23390 (1 mg/kg). The densities of Fos-, FosB-, Fra-1-, Jun- and JunD-immunoreactive nuclei induced by haloperidol and sulpiride in the hippocampus, piriform cortex and accumbens nucleus were higher than those in the control groups. The same regions showed higher densities of FosB-, Fra-1- and JunD-immunoreactive nuclei induced by SCH23390 compared with the control groups. We investigated further the activator protein-1 composite factors using super gel shift assays. These results suggested that induced Fos, FosB, Fra-1, Jun and JunD proteins constitute the activator protein-1 complex after the administration of haloperidol and sulpiride. In contrast, FosB, Fra-1 and JunD appear to constitute the activator protein-1 complex after the administration of SCH23390. Therefore, the diversity of activator protein-1 composite factors suggests that various kinds of gene are induced to act by some neuroleptics.
Insights
Neuroleptics like haloperidol and sulpiride, and dopamine D1 antagonist SCH23390, alter activator protein-1 (AP-1) complex formation in mouse brains. This suggests diverse AP-1 factors mediate neuroleptic drug actions.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The precise mechanisms linking neuroleptic drug actions to therapeutic effects remain unclear.
- Understanding these mechanisms is crucial for developing more effective treatments for neurological and psychiatric disorders.
Purpose of the Study:
- To investigate the expression of Fos- and Jun-related proteins and activator protein-1 (AP-1) DNA-binding activity in mouse brain following neuroleptic administration.
- To elucidate the specific AP-1 composite factors involved after treatment with haloperidol, (-)-sulpiride, and SCH23390.
Main Methods:
- Immunocytochemistry was used to detect Fos- and Jun-related proteins in specific brain regions of ddY mice.
- Super gel shift assays were employed to analyze AP-1 DNA-binding activity and identify composite factors.
Main Results:
- Haloperidol and (-)-sulpiride increased the density of Fos, FosB, Fra-1, Jun, and JunD immunoreactive nuclei in the hippocampus, piriform cortex, and accumbens nucleus.
- SCH23390 elevated FosB, Fra-1, and JunD immunoreactive nuclei in the same brain regions.
- AP-1 complexes were found to comprise Fos, FosB, Fra-1, Jun, and JunD after haloperidol/sulpiride treatment, and FosB, Fra-1, and JunD after SCH23390 treatment.
Conclusions:
- The findings indicate that neuroleptics induce the expression of various Fos and Jun proteins.
- The composition of AP-1 complexes differs depending on the specific neuroleptic drug administered.
- This diversity in AP-1 composite factors suggests varied gene induction pathways underlying the therapeutic actions of different neuroleptics.