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 [ 11 C]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 [ 11 C]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 [ 11 C]raclopride BP at each voxel. BP values were extracted from the t-map (threshold: t ¼ 4.2, equivalent to po0.05, 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 [ 11 C]raclopride binding was significantly different on the two test days in the ventral striatum (peak t ¼ 6.31; x ¼ À25, y ¼ À8, and z ¼ 0.1). In the t-map defined cluster, [ 11 C]raclopride BP values were 11.8 7 11.9% higher during the APTD session (po0.05). The reduction in d-amphetamine-induced DA release exhibited a linear association with the reduction in plasma tyrosine levels (r ¼ À0.82, po0.05). 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.

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Acute tryptophan depletion (ATD) studies indicate that low serotonin can lower mood and also increase aggression, although results vary somewhat between studies with similar participants. Lowering of mood after ATD is related to the susceptibility of the study participants to clinical depression, and some participants show no effect on mood. This indicates that low serotonin can contribute to lowered mood, but cannot—by itself—cause lowered mood, unless other unknown systems interact with serotonin to lower mood. Studies using tryptophan supplementation demonstrate that increased serotonin can decrease quarrelsomeness and increase agreeableness in everyday life. Social interactions that are more agreeable and less quarrelsome are associated with better mood. Thus, serotonin may have direct effects on mood, but may also be able to influence mood through changes in social behaviour. The increased agreeableness and decreased quarrelsomeness resulting from increases in serotonin will help foster congenial relations with others and should help to increase social support. As social support and social isolation have an important relationship with both physical and mental health, more research is needed on the implications of the ability of serotonin to modulate social behaviour for the regulation of mood, and for future physical and mental health.

Our results suggest that proneness to impulsivity, affective dysregulation, and reduced central 5-HT reuptake may (in part) be codetermined by the 5HTTLPR polymorphism. However, given inconsistent 5HTTLPR expression in different populations, we speculate that we may be observing a phenotype (i.e., eating disorder)-dependent manifestation.