Local cerebral glucose utilization (LCGU) was determined, using the quantitative autoradiographic [14C]2-deoxy-D-glucose technique, in 47 brain regions of awake rats, after acute and chronic haloperidol (HAL) administration (1 mg/kg or 1 mg/kg/day). LCGU was reduced in fewer regions after chronic HAL (19%) than after acute HAL (72%); the average reduction for all regions was smaller (8% and 25%, respectively). The reduced metabolic effect of chronic HAL is not due to a lower brain concentration of the drug, since similar effects on LCGU were found in rats which received an acute i.p. injection of HAL (as in the acutely treated animals) after chronic administration of HAL for 3 weeks. Furthermore, continuous infusion of HAL for 3 weeks or 1 day resulted in similar tolerance to the metabolic effect of HAL. Tolerance was not observed in the mesocortical dopamine (DA) system. The present findings show that tolerance develops to the effect of HAL on cerebral metabolism, even after 1 day of HAL treatment. Lack of tolerance in the mesocortical pathway may implicate this system in the neuroleptic effect of chronic HAL.