Decreasing Amphetamine-Induced Dopamine Release by Acute Phenylalanine/Tyrosine Depletion: A PET/[11C]Raclopride Study in Healthy Men

Abstract

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.

Lack of Effect of Tyrosine Depletion on Mood in Recovered Depressed Women

“…Indeed in a recent PET imaging of TYR depletion, we found that the increase in D 2 receptor binding as measured by [ 11 C]raclopride correlated significantly with the fall in the plasma ratio of TYR and PHE to large neutral amino acids (Montgomery et al, 2003). A similar finding was reported by Leyton et al (2004) who found that the ability of TYR depletion to attenuate the decrease in [ 11 C]raclopride binding produced by d-amphetamine correlated linearly with reduction in plasma TYR levels.…”

Dopamine and light: dissecting effects on mood and motivational states in women with subsyndromal seasonal affective disorder

“…However, microdialysis, 29 neuroendocrine 40 and fos expression studies 60 all suggest that APTD affects DA transmission over other catecholamines. Moreover, APTD has been shown to decrease extracellular DA levels in humans as indicated by increased striatal [ 11 C]raclopride binding in imaging studies 30,61 and to increase circulating prolactin levels (indicative of reduced DA function 62 ), but to have no effect on plasma melatonin, a neuroendocrine index of noradrenergic neurotransmission. 63 Finally, the sample size of 32 participants was modest, and only women were tested.…”

Acute Serotonin and Dopamine Depletion Improves Attentional Control: Findings from the Stroop Task

“…Acute tyrosine/phenylalanine depletion (ATPD) is a technique which has been shown to selectively decrease dopamine synthesis and release (Jaskiw and Bongiovanni, 2004;Leyton et al, 2004;McTavish et al, 1999aMcTavish et al, , 2001aMehta et al, 2005;Montgomery et al, 2003) and impair dopamine dependent cognitive processes such as working memory (Harmer et al, 2001;Harrison et al, 2004). To our knowledge, ATPD has never been used to investigate the effects of dopaminergic modulation on Stroop task performance.…”