Involvement of a c-fos-dependent mechanism in caffeine-induced expression of the preprotachykinin A and neurotensin/neuromedin N genes in rat striatum.
Striatal c-fos induction was blocked by local administration of phosphorothioated c-fos antisense oligonucleotides (AS-ODN) to examine the possible role of caffeine-induced c-fos expression in transcriptional regulation of striatal preproenkephalin, prodynorphin, preprotachykinin A and neurotensin/neuromedin N. Caffeine (100 mg/kg i.p.) induced both c-fos mRNA and Fos-protein, and this induction was significantly attenuated by intrastriatal injection of 4 (but not 1) nmol c-fos AS-ODN. This suggests that, in addition to translational arrest, other mechanisms may be involved in the mediation of antisense action. The action of the AS-ODN was sequence specific. The antisense blockade of c-fos reduced the effect of caffeine on the expression of mRNAs for preprotachykinin A and neurotensin/neuromedin N in the ventrolateral caudate-putamen. Levels of preproenkephalin and prodynorphin transcripts were unaffected. Thus caffeine induction of striatal preprotachykinin A mRNA and neurotensin/neuromedin N mRNA, but not of preproenkephalin mRNA or prodynorphin mRNA, may at least in part be mediated by a pathway involving Fos protein. The findings illustrate the utility of blockade of gene expression with antisense oligonucleotides for in vivo studies of drug actions.
Svenningsson
P
P
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Georgieva
J
J
Kontny
E
E
Heilig
M
M
Fredholm
B B
BB
D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D004745:Enkephalins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D008297:Male; D009496:Neurotensin / Q000096:biosynthesis*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000096:biosynthesis*; D011498:Protein Precursors / Q000096:biosynthesis*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015320:Tachykinins / Q000096:biosynthesis*; D013873:Thionucleotides; D014158:Transcription, Genetic / Q000187:drug effects*
D004745:Enkephalins; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D015320:Tachykinins; D013873:Thionucleotides; C044206:preprotachykinin; C042090:neuromedin N; D009496:Neurotensin; D002110:Caffeine; C033660:preproenkephalin