We have compared the ability of an acute injection of caffeine (3 mg/kg, i.p.) and long-term peroral caffeine consumption for 10 days (≈ 150 mg/kg/day in tap water) to affect cocaine self-administration in mice. The peak plasma and brain levels of caffeine and its metabolites were similar in the two experimental set-ups. Moreover, the levels reached are close to those obtained in humans upon coffee ingestion. Neither type of caffeine administration affected the reinforcing effect of cocaine, defined as a selective increase in nose-poke responses in mice self-administering cocaine compared to their yoked controls. However, caffeine injection increased the amount of cocaine self-administered whereas caffeine drinking reduced it. A low dose of cocaine, by itself essentially ineffective, produced an increase in c-fos and NGFI-A mRNA in the cerebral cortex in mice that had been drinking caffeine. An acute caffeine injection also enhanced the immediate early gene response to cocaine, but to a lesser degree. Cocaine and caffeine also synergistically increased NGFI-A expression in caudate-putamen. Thus, regular caffeine drinking decreased the cocaine intake without significantly affecting its reinforcing properties, perhaps because it enhanced the activation of the predominantly inhibitory frontal cortical areas produced by low doses of cocaine.