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Acute phenylalanine/tyrosine depletion (APTD) has been proposed as a new method to decrease catecholamine neurotransmission safely, rapidly, and transiently. Validation studies in animals are encouraging, but direct evidence in human brain is lacking. In the present study, we tested the hypothesis that APTD would reduce stimulated dopamine (DA) release, as assessed by positron emission tomography (PET) and changes in [11C]raclopride binding potential (BP), a measure of DA D2/D3 receptor availability. Eight healthy men received two PET scans, both following d-amphetamine, 0.3 mg/kg, p.o., an oral dose known to decrease [11C]raclopride BP in ventral striatum. On the morning before each scan, subjects ingested, in counter-balanced order, an amino-acid mixture deficient in the catecholamine precursors, phenylalanine, and tyrosine, or a nutritionally balanced mixture. Brain parametric images were generated by calculating [11C]raclopride BP at each voxel. BP values were extracted from the t-map (threshold: t=4.2, equivalent to p<0.05, Bonferroni corrected) and a priori identified regions of interest from each individual's coregistered magnetic resonance images. Both receptor parametric mapping and region of interest analyses indicated that [11C]raclopride binding was significantly different on the two test days in the ventral striatum (peak t=6.31; x=-25, y=-8, and z=0.1). In the t-map defined cluster, [11C]raclopride BP values were 11.8 ± 11.9% higher during the APTD session (p<0.05). The reduction in d-amphetamine-induced DA release exhibited a linear association with the reduction in plasma tyrosine levels (r = -0.82, p < 0.05). Together, the results provide the first direct evidence that APTD decreases stimulated DA release in human brain. APTD may be a suitable new tool for human neuropsychopharmacology research. [ABSTRACT FROM AUTHOR]