INCREASED EXPRESSION OF C-JUN, JUNB, AP-1, AND PREPROENKEPHALIN MESSENGER-RNA IN RAT STRIATUM FOLLOWING A SINGLE INJECTION OF CAFFEINE

The effect of a single injection of caffeine on the expression of c-fo s, c-jun, junB, and junD, on activator protein 1 (AP-1) and on the lev els of preproenkephalin mRNA in rat striatum was studied. Male rats we re given caffeine (25 mg/kg, 50 mg/kg, or 100 mg/kg, i.p.) and sacrifi ced at different times (0.5, 1, 2, 4, or 8 hr) after administration. B y using in situ hybridization of adjacent sections we found a rapid, t ransient, and dose-dependent increase of c-fos, c-jun, and junB by caf feine in striatum, especially in the lateral part. The induction peake d 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 i nduction of c-fos and c-jun, but not of junD, was seen in nucleus accu mbens. 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 admi nistration and was clearly increased after 4 hr. c-Fos, c-Jun, and Jun B proteins were components of the AP-1. There was also a dose-dependen t induction of preproenkephalin mRNA, which was most pronounced in the lateral and caudal part of striatum; the level peaked 4 hr after inje ction and was still significantly increased after 8 hr. In a complemen tary study we could not find increased binding to the AP-1-like site i n the 5'-flanking sequence of proenkephalin following caffeine treatme nt. The data show that a single dose of caffeine induces a temporally and spatially characteristic pattern of c-fos, c-jun, and junB inducti on, followed by changes in AP-1 and preproenkephalin mRNA. Thus, a sin gle 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 e arly genes and enkephalin could not be proven.