Regulation of cocaine-induced activator protein 1 transcription factors by the extracellular signal-regulated kinase pathway.
Extracellular signal-regulated kinases and activator protein 1 transcription factor have been functionally linked to addiction. It has also been shown that extracellular signal-regulated kinase activation can regulate cocaine-induced expression of c-Fos and FosB, two possible components of activator protein 1. A direct link between extracellular signal-regulated kinases and activator protein 1 activation has, however, remained unexplored. In this study, we investigated the role of extracellular signal-regulated kinases in the regulation of DNA-binding activity and composition of activator protein 1 induced in the mouse caudate putamen by cocaine treatment. We have found that pre-treatment with SL327, a selective inhibitor the extracellular signal-regulated kinase pathway, has no influence on cocaine-induced DNA-binding activity of activator protein 1, when examined one hour after an acute cocaine treatment. This phenomenon results from simultaneous decrease of c-Fos protein level and increases in JunB and deltaFosB protein levels. SL327 pre-treatment, however, reduces the DNA-binding activity of the activator protein 1 complex induced six hours after an acute cocaine treatment as well as one hour after the last of the chronic cocaine injections, a phenomenon that results from the concomitant reduction of all cocaine-induced proteins (c-Fos, FosB, deltaFosB, JunB). In conclusion, we have found that extracellular signal-regulated kinase inhibition may not only interfere with cocaine-induced gene expression and activator protein 1 complex activation, but may also disturb the time-course of gene expression and composition of activator protein 1 complex. Our results support the notion that inhibitors of the extracellular signal-regulated kinase pathway could be valuable tools to obliterate cocaine-induced molecular changes and the development of addiction.
Radwanska
K
K
Laboratory of Molecular Neurobiology, Nencki Institute, Pasteura 3, 02 093 Warsaw, Poland.
Valjent
E
E
Trzaskos
J
J
Caboche
J
J
Kaczmarek
L
L
D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism*
D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; C424127:SL 327; D018808:Transcription Factor AP-1; D000607:Aminoacetonitrile; D048049:Extracellular Signal-Regulated MAP Kinases; D003042:Cocaine