The quantitative [14C]2-deoxyglucose autoradiographic method was used to study the effects of the acute administration of 10 mg/kg of caffeine and 0.1 mg/kg of L-phenylisopropyladenosine (LPIA) given separately or in combination. After an injection of caffeine, the local cerebral metabolic rates for glucose (LCMRglu) were increased in 34 out of 61 structures studied, mainly in monoaminergic cell groupings, the thalamus and structures belonging to the extrapyramidal motor system. The administration of LPIA decreased the LCMRglu in 30 out of 61 structures studied. These areas were essentially monoaminergic cell groupings, structures of the extrapyramidal motor system and all hypothalamic areas. After a combined injection of caffeine and LPIA, the LCMRglu was either increased or not changed in structures affected by caffeine or LPIA given alone. The results of the present study indicate that, even if caffeine and LPIA compete for the occupation of adenosine receptors, the effects of these two substances on the energy metabolism of the brain are partly mediated by peripheral mechanisms.