We have recently shown that repeated exposure to caffeine sensitizes rats to the motor activating effects of dopamine D(1) and D(2) receptor agonists. In order to study the role of dopamine in this effect, sensitization to caffeine and cross-sensitization between caffeine and amphetamine was evaluated by studying turning behavior and in vivo striatal dopamine release in unilaterally 6-hydroxydopamine-lesioned rats. Administration of caffeine (15 mg/kg) for 2 weeks, on alternate days, induced a significant increase in ipsilateral turning behavior during the course of treatment, indicating that sensitization to caffeine took place in the intact striatum. Caffeine modestly increased dopamine release in the intact dorsa-lateral striatum and no significant difference between the first (+38%) and the last (+51%) injection was observed. Amphetamine (2 mg/kg) induced a significantly higher ipsilateral turning behavior in caffeine-sensitized rats than in vehicle-pretreated rats, however, a similar increase in dopamine release (+900 and +800%) was observed in the two groups. The results are the first demonstration that caffeine pre-exposure sensitizes the motor-stimulant effects of caffeine itself and of amphetamine. Sensitized ipsilateral turning after caffeine and amphetamine are not correlated to modification in striatal dopamine release, rather, postsynaptic modifications in dopamine and adenosine receptor interaction might be involved in the sensitization phenomena observed.