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ratio to LNAAs in the range of 80-90%. Unequivocal differences in the elicited behavioral effects have not been identified. Direct comparisons between the two mixtures, though, have not been conducted.

The McGill group has also developed a version of the APTD mixture for use in vervet monkeys. The formula is identical to that used in humans, though adjusted accordingly for the monkey's lower body weight. At least two versions for use in rodents have also been described, and they can be administered by gavage or intraperitoneal injection. Again, direct comparisons of their effects have not been reported but unequivocal differences are not evident in the literature.

Advantages and Disadvantages of APTD

Compared with the other methods for decreasing DA transmission, APTD has both advantages and disadvantages. On the plus side, the effects develop and dissipate rapidly, beginning as soon as 3 h after ingestion and disappearing three to four hours later. Transient nausea is sometimes reported, and 5-10% of subjects will regurgitate the mixture, but these sensations subside. Experience suggests that subjects who retain the mixtures for a minimum of 45-60 min achieve a decrease in plasma phenylalanine and tyrosine levels within the usual range. These mild adverse effects compare well to those associated with other methods for decreasing DA transmission. For example, administration of the competitive TH inhibitor, a-methyl-para-tyrosine (AMPT) typically requires 48-72 h inpatient observation, and can lead to motor dyskinesias and crystalluria. The former effect likely reflects large DA depletions within the nigrostriatal pathway, and this can be either an advantage or a confound depending on the outcome of interest. DA receptor antagonists can also be used. Positron emission tomography ► PET imaging studies suggest that receptor blockade up to 70% or 80% can be achieved without eliciting extrapyramidal side effects or hyper-prolactinemia, but available compounds either do not bind to all DA receptor subtypes or are nonspecific, binding also to multiple non-DA receptors.

Neurophysiological Effects of APTD

► Microdialysis studies conducted in rats suggest that APTD does not affect extracellular DA levels when animals are tested at rest, but potent effects are seen during

Acute phenylalanine/tyrosine depletion (APTD)

BAL + Amphetamine

Phenylalanine and Tyrosine Depletion. Fig. 2. The figure depicts functional neuroimaging evidence that acute phenylalanine/ tyrosine depletion (APTD) decreases extracellular dopamine levels in human striatum. At left, the colored t-map superimposed on the anatomical magnetic resonance image delineates regions where binding of the D2/D3 receptor ligand [11C]raclopride was significantly higher following APTD versus ingestion of a nutritionally balanced control mixture (BAL), indicative of decreased extracellular dopamine levels (Montgomery et al. 2003). The image at right shows regions where [11C]raclopride binding was higher on a test day with amphetamine plus APTD, as compared to amphetamine plus BAL, indicative of decreased drug-induced dopamine release (Leyton et al. 2004). Both effects occurred primarily within more ventral than dorsal regions of the striatum. The right side of each image represents the right side of the brain.

periods of increased DA cell firing (Jaskiw and Bongiovanni 2004) or release (McTavish et al. 1999b). These effects are dose-dependent, and APTD can diminish stimulated DA release by up to 70% (McTavish et al. 1999b). In humans, APTD increases circulating levels of prolactin, a neuroendocrine index of decreased DA transmission within the tuberoinfundibular pathway. In functional neuroimaging studies, APTD also decreases striatal DA release (Fig. 2), and this has been seen in the absence of an experimental challenge (Montgomery et al. 2003); however, whether this reflects a decrease in resting DA release or a diminished response to the mild stress of having an hour-long brain scan is difficult to disentangle. Irrespective, larger changes are reported to occur when participants are given a pharmacological challenge; that is, APTD decreases amphetamine-induced DA release, and the magnitude of this effect is twice of what is seen in subjects tested at "rest" (Leyton et al. 2004). One consequence of the APTD-induced decrease in DA transmission appears to be a disruption in the ability of different components of cortical-subcortical neurocircuits to work in coordination; that is, whereas cortical and basal ganglia structures exhibit high intercorrelations in activity levels when participants are engaging in a familiar neuro-cognitive task, these correlations are significantly reduced following APTD (Nagano-Saito et al. 2008). Based on these observations, it was proposed that normal DA tone is required to permit the efficient transfer of information throughout cortico-striatal circuitry.

Neurocognitive Effects of APTD

The APTD literature remains relatively small, but a number of behavioral effects have been reported. These include changes in the ability of subjects to preferentially respond to reward-related cues, to adjust responding appropriately when reward parameters change, and to sustain selective, focused interest in affectively relevant events. Some studies have also identified effects on spatial working memory, but an equal number of published studies yielded negative results; functional neuroimaging studies suggest that the variable results might reflect individual differences in the magnitude of DA depletion achieved.

Effects of APTD on Mood and Motivational States

APTD alone does not appear to lower mood in healthy individuals. In comparison, a now replicated finding is that APTD potentiates the mood-lowering effect of a psychological challenge. In people with mood disorders, a dissociation is seen also; tyrosine depletion reduces manic symptoms in bipolar patients but does not reinstate depressive symptoms in recovered patients with a history of major depression.

Effects of APTD on Substance Use

A frequent application of the APTD method has been in addiction research. APTD is reported to decrease psychostimulant effects of amphetamines, the ability of ► cocaine and cocaine-paired cues to elicit ► craving, alcohol self-administration in a free-choice task when the participants are light social drinkers, and the tendency to sustain responding on a ► progressive ratio breakpoint task for successive units of an alcoholic beverage when the participants are heavy social drinkers. In comparison, in nicotine-dependent smokers the results have been quite variable.

McTavish SF, Cowen PJ, Sharp T (1999b) Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release. Psychopharmacology (Berl) 141:182-188 Montgomery AJ, McTavish SF, Cowen PJ, Grasby PM (2003) Reduction of brain dopamine concentration with dietary tyrosine plus phenyl-alanine depletion: an [11C]raclopride PET study. Am J Psychiatry 160:1887-1889

Nagano-Saito A, Leyton M, Monchi O, Goldberg Y, He Y, Dagher A, (2008) Dopamine facilitates fronto-striatal functional connectivity during a set-shifting task. J Neurosci 28(14):3697-3706 Palmour RM, Ervin FR, Baker GB, Young SN (1998) Effects of acute tryptophan depletion and acute tyrosine/phenylalanine depletion on CSF amine metabolite levels and voluntary alcohol consumption in vervet monkeys. Psychopharmacology 136:1-7 Wurtman RJ, Larin F, Mostafapour S, Fernstrom JD (1974) Brain catechol synthesis: control by brain tyrosine concentration. Science 185 (146):183-184

Conclusions

Overall, the APTD method has proven to be an effective method to decrease DA transmission in human brain. Although, the effects might be smaller than those produced by other methods, the rapid, transient, and selective effects as well as more modest side effect profile are compelling for ethical reasons and simplify the interpretation of results.

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