Chronic administration of uridine alters dopaminergic activity and related behavior. The present study investigated this effect using amphetamine and cocaine-induced activity and rotation in rats with unilateral dopaminergic lesions. Adult, female Sprague-Dawley rats with free access to food and water received daily intraperitoneal uridine (16 mg/kg) or an equal volume of saline. Activity was assessed for 10 min in a photocell chamber 30 min after intraperitoneal amphetamine or cocaine and 4 hr after the uridine or saline. Additional rats with unilateral dopaminergic lesions were treated comparably and assessed for stimulant-induced rotation. Uridine exerted no effect on body weight, activity, or rotation under baseline conditions. At higher doses, amphetamine and cocaine decreased activity and caused a dose-dependent increase in rotations. In the activity test, uridine-treated rats exhibited a significant increase in sensitivity to amphetamine but not to cocaine. In the rotation test, uridine-treated rats showed increased sensitivity to both stimulants. Finally, neurochemical analysis of a third set of comparably treated rats revealed that uridine blunted the amphetamine-induced increase in striatal dopamine. These observations are interpreted as indicating that chronic uridine modulates the stimulant-induced release of dopamine and, therefore, may be of therapeutic interest.