Increased expression of c-jun, junB, AP-1, and preproenkephalin mRNA in rat striatum following a single injection of caffeine.
The effect of a single injection of caffeine on the expression of c-fos, c-jun, junB, and junD, on activator protein 1 (AP-1) and on the levels of preproenkephalin mRNA in rat striatum was studied. Male rats were given caffeine (25 mg/kg, 50 mg/kg, or 100 mg/kg, i.p.) and sacrificed at different times (0.5, 1, 2, 4, or 8 hr) after administration. By using in situ hybridization of adjacent sections we found a rapid, transient, and dose-dependent increase of c-fos, c-jun, and junB by caffeine in striatum, especially in the lateral part. The induction peaked after 1 hr, but persisted for 2 hr, and in the case of junB for 4 hr. No induction of junD was found. A strong induction of junB, a weak induction of c-fos and c-jun, but not of junD, was seen in nucleus accumbens. Furthermore, by using gel shift assay we found an induction of AP-1 by caffeine (100 mg/kg) in striatum, which peaked 2 hr after administration and was clearly increased after 4 hr. c-Fos, c-Jun, and JunB proteins were components of the AP-1. There was also a dose-dependent induction of preproenkephalin mRNA, which was most pronounced in the lateral and caudal part of striatum; the level peaked 4 hr after injection and was still significantly increased after 8 hr. In a complementary study we could not find increased binding to the AP-1-like site in the 5'-flanking sequence of proenkephalin following caffeine treatment. The data show that a single dose of caffeine induces a temporally and spatially characteristic pattern of c-fos, c-jun, and junB induction, followed by changes in AP-1 and preproenkephalin mRNA. Thus, a single dose of caffeine causes changes in gene transcription in the brain that may be related to the adaptive changes that occur after caffeine administration. However, a direct causal link between the immediate early genes and enkephalin could not be proven.
Svenningsson
P
P
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Ström
A
A
Johansson
B
B
Fredholm
B B
BB
D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004745:Enkephalins / Q000096:biosynthesis*; D015870:Gene Expression / Q000187:drug effects*; D016758:Genes, jun; D017403:In Situ Hybridization; D007274:Injections, Intraperitoneal; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D011498:Protein Precursors / Q000096:biosynthesis*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000096:biosynthesis* / Q000378:metabolism
D004745:Enkephalins; D009838:Oligodeoxyribonucleotides; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D002110:Caffeine; C033660:preproenkephalin