The human striatum is functionally organized into limbic, associative, and sensorimotor subdivisions, which process information related to emotional, cognitive, and motor function. Dopamine projections ascending from the midbrain provide important modulatory input to these striatal subregions. The aim of this study was to compare activation of dopamine D2 receptors after amphetamine administration in the functional subdivisions of the human striatum. D2 receptor availability (V3") was measured with positron emission tomography and [11C]raclopride in 14 healthy volunteers under control conditions and after the intravenous administration of amphetamine (0.3 mg/kg). For each condition, [11C]raclopride was administered as a priming bolus followed by constant infusion, and measurements of D2 receptor availability were obtained under sustained binding equilibrium conditions. Amphetamine induced a significantly larger reduction in D2 receptor availability (DeltaV3") in limbic (ventral striatum, -15.3 +/- 11.8%) and sensorimotor (postcommissural putamen, -16.1 +/- 9.6%) regions compared with associative regions (caudate and precommissural putamen, -8.1 +/- 7.2%). Results of this region-of-interest analysis were confirmed by a voxel-based analysis. Correction for the partial volume effect showed even greater differences in DeltaV3" between limbic (-17.8 +/- 13.8%), sensorimotor (-16.6 +/- 9.9%), and associative regions (-7.5 +/- 7.5%). The increase in euphoria reported by subjects after amphetamine was associated with larger DeltaV3" in the limbic and sensorimotor regions, but not in the associative regions. These results show significant differences in the dopamine response to amphetamine between the functional subdivisions of the human striatum. The mechanisms potentially accounting for these regional differences in amphetamine-induced dopamine release within the striatum remain to be elucidated, but may be related to the asymmetrical feed-forward influences mediating the integration of limbic, cognitive, and sensorimotor striatal function via dopamine cell territories in the ventral midbrain.