It has previously been shown that caffeine, in a dose-dependent manner, increases the expression of the protooncogene c-fos in the rat brain, predominantly in the caudate-putamen and tuberculum olfactorium. In this study we examined the effect of related xanthines and of selective phosphodiesterase inhibitors on c-fos expression. The effect of caffeine (75 mg kg-1) was mimicked by 3-isobutyl-1-methyl xanthine (IBMX) (25 mg kg-1) and theophylline (100 mg kg-1) but not by 8-p-sulfophenyltheophylline (10 mg kg-1), enprofylline, theobromine or paraxanthine (each at 100 mg kg-1). Moreover, the cyclic AMP-selective phosphodiesterase inhibitors rolipram (10 or 20 mg kg-1) and SQ 20,006 (25 mg kg-1) and the cyclic GMP-selective phosphodiesterase inhibitor zaprinast (10 mg kg-1) failed to induce c-fos in striatum, but caused a clear-cut induction in the overlying cerebral cortex. Thus, c-fos is induced in rat striatum following administration of caffeine and other xanthines that (provided they enter the brain) block adenosine receptors, suggesting an involvement of central adenosine receptors. Inhibition of cyclic nucleotide phosphodiesterase does not appear to play any important role in c-fos induction by the xanthines.