Dexamethasone attenuates kainate-induced AP-1 activation in rat brain.
The goal of this investigation was to determine if administration of the synthetic glucocorticoid dexamethasone modulates rat brain AP-1 DNA binding activity. Treatment with the selective excitatory amino acid agonist kainate was used to activate AP-1 formation. Kainate (12 mg/kg) administration induced a biphasic activation of AP-1 in rat cerebral cortex and hippocampus with maximal levels observed at 1.5 h and 4.5 h and lower levels at 3 h and 6 h. Kainate also induced biphasic increases in the concentrations of some of the AP-1 constituent proteins (immediate early gene protein products), with initial increases of c-Jun, Fos, and Jun B occurring at 1.5 h and secondary larger increases at 4.5 h, but the level of Jun D was not altered by kainate treatment. Pretreatment with dexamethasone (1 mg/kg) reduced AP-1 activity at both 1.5 h and 4.5 h after kainate administration in both brain regions. Dexamethasone pretreatment did not modify the concentrations of the AP-1 constituent proteins obtained after kainate administration except for a reduction of Jun B levels 1.5 h after kainate. These results demonstrate that elevated glucocorticoid levels reduce the stimulation by kainate of AP-1 activity in rat cortex and hippocampus without causing corresponding decreases in the levels of immediate early gene proteins. Binding of the activated glucocorticoid receptor to c-Jun or Fos is likely to contribute to the decreased AP-1 DNA binding activity following dexamethasone treatment.
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Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham 35294-0017.
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D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects*; D006624:Hippocampus / Q000378:metabolism; D007608:Kainic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000378:metabolism*
D009838:Oligodeoxyribonucleotides; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D003907:Dexamethasone; D007608:Kainic Acid