![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
4 Departments of Psychiatry, 5 Pharmacology, 6 Surgery, and 7 Epidemiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
* To whom correspondence should be addressed. E-mail: fernstromjd{at}upmc.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT LITERATURE CITED |
|---|
This review will consider the evidence that precursor supply modifies monoamine production and the physiologic factors that influence this relation, focusing on the Tyr-catecholamine relation. Consideration will be given to the role of Phe in catecholamine synthesis in support of the idea that this amino acid functions as a cosubstrate with Tyr for Tyr hydroxylase (TH) and is not an inhibitor of this enzyme in vivo at normal and even high concentrations. Brain functions influenced by Tyr-mediated changes in catecholamine synthesis will also be discussed.
Tyr availability affects catecholamine synthesis rate
Catecholamines are synthesized from Tyr (Fig. 1). The initial step involves hydroxylation to dihydroxyphenylalanine (DOPA), catalyzed by the enzyme TH. Once formed, DOPA is rapidly decarboxylated to DA by aromatic L-amino acid decarboxylase. In neurons that use DA as a transmitter, no further enzymatic modification occurs. Neurons that use NE as a transmitter contain an additional enzyme, DA-ß-hydroxylase, that converts DA to NE. Neurons using epinephrine as a transmitter contain 1 additional enzyme, phenylethanolamine-N-methyl transferase, which is responsible for catalyzing the conversion of NE to epinephrine. The initial step in the pathway, Tyr hydroxylation, is rate limiting and thus controls the rate of synthesis through the entire pathway (3,4). Early work established that this enzyme was subject to end-product inhibition (by any of the above products) as examined either in vitro using enzyme preparations (4) or in vivo, such as by following the rate of 14C-Tyr conversion to 14C-catecholamine in the brains of rats treated with a drug to raise endogenous catecholamine concentrations (e.g. a monoamine oxidase inhibitor) (5). Later work established that TH was subject to a number of other controls, including a rapid phosphorylation-linked activation of enzyme during periods of increased neuronal activity (6) (i.e. synthesis increases at times of greater neuronal demand).
|
|
|
50% over this range of protein intakes (Table 3). A number of points should be made from these observations. First, variations in Tyr supply affect not just Tyr hydroxylation (DOPA synthesis) rate; studies by others indicate that they affect overall catecholamine production and release (19–21), suggesting functional consequences. Second, because DOPA synthesis varied directly with Tyr level in hypothalamus, the bulk of the catecholamine terminals in hypothalamus must be active under the conditions examined. Third, unlike the retina in which the dominant catecholamine is DA, hypothalamus contains terminals of DA, NE, and epinephrine neurons. Hence, whereas an effect on DOPA synthesis in the retina implies an action in DA neurons, an effect on DOPA synthesis in hypothalamus could be in any or all of the catecholamine terminals in this region. At present, we do not know which catecholamine neurons are affected. And fourth, although it is unclear why retinal DA neurons should be sensitive to dietary protein ingestion via effects on local Tyr concentrations, it is of interest physiologically that such an effect occurs on hypothalamic catecholamine nerve terminals, because these neurons are involved in appetite control (22). What might the connection be? One speculation relates to dietary protein adequacy in animals (including humans) that occupy environments in which protein availability normally varies markedly, requiring them to be able to sense and obtain adequate protein supplies. In mature rats, the maintenance protein requirement is 5–7% (percent energy) (23). The range of protein intake that is associated with a linear relation to hypothalamic Tyr levels and DOPA synthesis is 2–10%, a range that brackets the maintenance protein requirement. Conceivably, therefore, the changes in Tyr levels and DOPA (and overall catecholamine) synthesis produced in hypothalamus (and perhaps elsewhere in the brain) by the ingestion of different levels of dietary protein could be a signal to appetite control circuitry regarding dietary protein adequacy. In nature, animals experience circadian and circannual variations in dietary protein intake. For example, nonhuman primates, studied in their natural environments, have been shown to vary above and below their protein requirement, depending on the time of year and the availability of protein sources in the environment (24). Moreover, although data are more limited, rats in their native habitats appear to consume protein in amounts that place their intakes modestly above requirement levels (25). In natural environments, mechanisms that provide information to the brain regarding dietary protein status would be extremely useful in helping animals to optimize foraging efficiency to ensure adequacy of protein intake over time.
|
When TH was initially purified and characterized (in brain and adrenal) and its kinetic properties studied in vitro using a synthetic pterin cofactor (6,7-dimethyltetrahydropterin), the enzyme was found to hydroxylate Phe, but only at a small fraction of the rate at which it hydroxylated Tyr (26). In addition, Phe was observed to inhibit Tyr hydroxylation (26). When subsequently examined using the natural pterin cofactor, tetrahydrobiopterin, the enzyme was found to hydroxylate Phe at a rate comparable to that of Tyr. Moreover, whereas Tyr was found to inhibit enzyme activity at high concentrations (dubbed substrate inhibition), Phe did not show this effect (27). The investigators were surprised by the extent to which TH could hydroxylate Phe and wondered if Phe might not be the preferred substrate for the enzyme. And, in light of the findings, they also questioned whether the reduction in catecholamines reported in subjects with classical phenylketonuria (PKU), who have extremely high Phe concentrations in blood and tissues, was due to Phe inhibition of TH (27). Subsequently, the hydroxylation of radioactively labeled Phe to DOPA was demonstrated in synaptosomes (a preparation of nerve endings) from brain tissue and linked directly to TH [because the effect was blocked by pretreatment of synaptosomes with a known TH inhibitor and Phe hydroxylase is not present in brain (28,29)]. Suggestive evidence also exists that Tyr was the preferred substrate (29–31).
If Phe is as good a substrate for TH as is Tyr, has a Km for the enzyme that is in the range of that for Tyr (29) and also in the range of Phe concentrations found in vivo, and shows no substrate inhibition, then raising Phe concentrations in vivo in the brain might stimulate DOPA synthesis in a manner similar to that seen in response to raising Tyr concentrations (10). We studied this possibility using the retinal DA model system in which Tyr administration rapidly stimulates DOPA synthesis (Tyr hydroxylation) in light-adapted rats (10). However, in normal rats, Phe administration leads to an immediate rise in circulating Tyr concentrations (the result of an active Phe hydroxylating capacity in liver), causing retinal Phe and Tyr levels to rise. Because a rise in retinal Tyr stimulates DOPA synthesis, a convincing evaluation of the ability of an increase in retinal Phe to enhance DOPA synthesis could not be conducted in normal animals. This complication, however, was eliminated by pretreating rats with an inhibitor of Phe hydroxylase, p-chlorophenylalanine. In such animals, an injection of Phe was found to increase retinal Phe but not Tyr concentrations (Table 4). Of particular interest, while a large rise in retinal Tyr concentrations, produced by injecting this amino acid, stimulated DOPA synthesis in p-chlorophenylalanine-pretreated rats, a similarly large rise in retinal Phe failed to stimulate DOPA synthesis (Table 4) (32). This finding is somewhat surprising but might be explicable if Tyr were the preferred substrate for the hydroxylase enzyme. As noted above, this possibility was suggested by work in synaptosomes, showing that Tyr more effectively inhibited labeled Phe conversion to labeled DOPA than did Phe labeled Tyr to labeled DOPA (29,30).
|
|
|
25 µmol/L, a value similar to that observed by others (34). In comparison, brain Tyr concentrations in vivo typically vary between 50 and 200 µmol/L (13) (Table 3). When incubations are then conducted in the presence of different concentrations of unlabeled Phe, ranging from 1 to 300 µmol/L, the appearance of 3H-DOPA from 3H-Tyr does not begin to drop until Phe concentrations reach 60 µmol/L (Fig. 3H). And, although suppression of 3H-DOPA synthesis from 3H-Tyr is notable at 60 and 300 µmol/L, it is not complete, and indeed, at 100 µmol/L Tyr, DOPA synthesis from Tyr accounts for almost 100% of total DOPA synthesis (compare panels I and J of Fig. 3 at 100 µmol/L Tyr). It should also be noted in the left panels of Figure 3 that as medium Phe concentration rises, no inhibition of DOPA synthesis is evident; indeed, the addition of Phe raises DOPA synthesis at low medium Tyr concentrations and also at high medium Tyr concentrations (compare panels A and I in Fig. 3). As noted above, at high medium Tyr concentrations, Phe probably has this effect by blocking cellular Tyr uptake, thereby keeping intracellular Tyr concentrations low (35).
From these results in PC-12 cells, we can hazard an interpretation of the findings in the animal studies in which Phe injection appeared to have no effect on retinal DOPA synthesis (Table 4). First, normal retinal Phe and Tyr concentrations are in the 2–4 nmol/mg protein range, which is 400 µmol/L Phe and 300 µmol/L Tyr (calculated from data in Table 4). When retinal Phe is increased 3-fold by Phe injection (to 1200 µmol/L), no increase in DOPA synthesis is evident. From the PC-12 cell studies, intracellular Phe concentrations reach 1100 µmol/L when medium Phe concentration is 300 µmol/L (35). Intracellular Tyr concentrations approximate 300 µmol/L when medium Tyr concentrations are between 10 and 100 µmol/L in the presence of 300 µmol/L Phe (35). From Figure 2H,J, it is clear that at these concentrations of Phe and Tyr very little DOPA is being synthesized from Phe. Hence, if a comparison between PC-12 cells and retina is valid, almost all DOPA synthesized in retina is derived from Tyr at normal retinal Tyr concentrations regardless of the retinal Phe concentration. Accordingly, variations in retinal Phe would be predicted to have little impact on total DOPA synthesis in retina. However, it should be noted that if the same analysis is applied to the stimulation of retinal DOPA synthesis by an injection of Tyr, which raises retinal Tyr concentrations from 3–13 nmol/mg protein (300–1200 µmol/L) in the presence of 300–400 µmol/L Phe (Table 4), the PC-12 cell results do not predict stimulation of DOPA synthesis by Tyr. That is, 300–400 µmol/L intracellular Phe is obtained when medium Phe concentrations are 60 µmol/L. An increase from 300 to 1200 µmol/L intracellular Tyr occurs when medium Tyr is raised from 10 to 100 µmol/L (35). However, total DOPA synthesis declines when medium Tyr is increased from 10 to 100 µmol/L at a medium Phe concentration of 60 µmol/L (Fig. 3G), which clearly stands in contrast to the rise in retinal DOPA synthesis produced by Tyr injection (Table 4). A satisfactory explanation for this difference is lacking. Indeed, more generally, if substrate inhibition by Tyr is a real phenomenon in vivo, no satisfactory explanation with supporting data to our knowledge has yet been offered that indicates why raising Tyr concentrations (whether by injection or via the diet) can accelerate catecholamine synthesis (and release) by neurons. Moreover, if the Km of TH for Tyr is 25 µmol/L (see above), normal tissue Tyr concentrations are 50–200 µmol/L, and Tyr levels producing a rise in Tyr hydroxylation rate in activated neurons reach 1,000 µmol/L or more, it is difficult to imagine how this rise in substrate level could enhance the degree of Tyr saturation of TH sufficiently to produce this effect, because the enzyme should already be almost fully saturated. One hypothesis might be that the local intracellular Tyr pool available to TH differs from and is lower than that elsewhere in the neuron (e.g. when the neurons and TH are activated, Tyr utilization by TH increases markedly and local Tyr concentrations fall) (10), although this possibility has not been carefully evaluated.
Finally, it is of interest to consider whether and under what conditions Phe can inhibit Tyr hydroxylation (DOPA synthesis). In the rat retinal study discussed above (32), a Phe-DOPA synthesis dose-response study was also conducted and a significant inhibition of retinal DOPA synthesis was observed at a retinal Phe concentration of 1660 µmol/L. This concentration exceeds that reached in the PC-12 cell studies discussed above, making them of no use in assessing if substrate inhibition has emerged at such high Phe concentrations. But in recent studies assessing brain Phe concentrations in the brains of subjects with classical PKU (homozygous) using magnetic resonance spectroscopy, Phe concentrations ranged to only 900 µmol/L (36). These concentrations are considerably lower than those associated with inhibition of DOPA synthesis in retina. Hence, this comparison supports the notion advanced previously by Kaufman and associates (27) that if PKU is associated with diminished catecholamine synthesis, the effect may be unrelated to a direct inhibition of TH by Phe.
Functional effects of Tyr-induced changes in catecholamine synthesis
Because Tyr administration stimulates catecholamine synthesis in the brain, a number of functions have been examined that might be anticipated to be affected, including blood pressure and the secretion of pituitary hormones. Dosing with the amino acid was found to reduce blood pressure in hypertensive rats (37) and to inhibit the secretion of the pituitary hormone prolactin in rats pretreated with reserpine (38), both expected effects based on a stimulation of NE and DA synthesis/release, respectively. Tyr administration has also been reported to improve working memory under stressful conditions in humans, an effect also linked to catecholamines (39), and to improve swim time in hypothermic rats, given alone or in combination with catecholamine releasing agents (e.g. amphetamine; swim time provides a measure of "behavioral despair," a preclinical measure useful in assessing the antidepressant efficacy of drugs) (40). Although this latter effect in rats implied that Tyr might be useful in the treatment of depression (by raising catecholamine synthesis and release), the amino acid did not show a positive effect when tested in a double-blind study in depressed human subjects (41). Tyr administration to rats has been shown to increase neuronal catecholamine release in corpus striatum (DA) (42) and hippocampus (NE) (40) using in vivo microdialysis.
More recently, functional effects have been studied in relation to rapid reductions in brain Tyr levels using a treatment that reduces Tyr transport into brain. Tyr is transported across the BBB by a carrier that it shares with a number of other LNAA, including tryptophan, Phe, and the branched-chain amino acids (leucine, isoleucine, and valine). Because this LNAA carrier is competitive and plasma concentrations of the LNAA approximate their Km for the carrier (43), raising the blood levels of 1 or more LNAA can reduce the uptake into brain of other LNAA and lower their brain concentrations. Thus, reducing Tyr levels in brain can be accomplished by providing an oral dose of the LNAA lacking Tyr and Phe (Phe is immediately hydroxylated to Tyr in the liver). In practice, a mixture has been used that contains amino acids in addition to the LNAA, because this combination lowers plasma concentrations of Tyr (an effect originally unanticipated) while raising those of the other LNAA, thus enhancing the antagonism of competitive Tyr transport across the BBB (44,45). When this mixture of amino acids was given to rats orally, circulating Tyr concentrations declined rapidly, whereas those of the other LNAA rose, producing a marked reduction in brain Tyr concentration that persisted for several hours. Association with these changes are reductions in Tyr hydroxylation rate and DA turnover in brain regions (44,45). For example, we observed this treatment to reduce Tyr hydroxylation rate in retina and hypothalamus (Table 5) and others have observed this effect in other brain regions into which catecholamine terminals project (corpus striatum, nucleus accumbens, prefrontal cortex, and hippocampus) (20). Some evidence suggests that this Tyr depletion paradigm may also work in humans to reduce DA release; the effect is inferred from a change in 11C-raclopride binding in corpus striatum, using positron emission tomography (46) (raclopride is a DA receptor ligand). In rats, Tyr depletion by itself does not appear to reduce DA (prefrontal cortex) or NE (hippocampus) release, measured using in vivo microdialysis (20,47). However, it does reduce the increase in DA and NE release produced by drugs that either block catecholamine reuptake or receptors (20,47) and attenuates in rats the behavioral activation produced by amphetamine, a catecholamine-releasing agent (48).
|
Summary and conclusions
A considerable body of data supports the links between Tyr concentrations in catecholamine neurons in brain/retina, Tyr hydroxylation rate, and overall catecholamine synthesis and neuronal release. Moreover, a number of physiological and behavioral functions are predictably modified as a result. These relations are thought to exist only in active neurons. Despite the convincing findings, however, this substrate-product relation has never been reconciled with the observation that the Km of TH for Tyr is considerably below endogenous Tyr concentrations. TH should thus be almost fully saturated with substrate; based on this fact alone, one would not predict that raising Tyr concentrations would stimulate Tyr hydroxylation. Neuronal activation, a precondition for Tyr to be able to influence hydroxylation rate, does not increase Tyr Km [e.g. (6,54)]. Reduced substrate affinity is thus not an explanation. The only other possible explanation might be a reduction in Tyr concentrations in the vicinity of TH molecules when neurons have been activated and Tyr hydroxylation rate markedly increased. Whereas some data suggest that such might be the case (55), other data disagree [e.g. Tyr levels in PC-12 cells show no obvious reduction in high potassium vs. low potassium medium; hydroxylation rate is markedly stimulated in high potassium (35)]. Hence, an exact accounting of the mechanism by which changes in Tyr concentrations modify hydroxylation rate and catecholamine synthesis has yet to be provided. An explanation is also lacking that resolves the conflict between the concept of substrate inhibition of TH by Tyr and the ability of increases in Tyr concentration to stimulate Tyr hydroxylation rate.
Phe is also a substrate for TH. However, based on PC-12 cell studies, Tyr is the preferred substrate, except when Tyr concentrations are unusually low, a phenomenon unlikely to occur physiologically (because in mammals, ingested Phe is rapidly hydroxylated to Tyr in the liver and provided to the circulation). Hence, physiologically, DOPA synthesis is likely to derive primarily from the hydroxylation of Tyr, not Phe. Phe has been argued to be an inhibitor of TH in vivo (56). And yet, the evidence is very weak that Phe inhibits TH; indeed, evidence is much stronger that Phe does not inhibit TH, even at extremely high concentrations. Even when apparent inhibition of DOPA synthesis can be linked to high Phe concentrations, the Phe concentrations achieved are considerably higher than even those extremely high values observed in the brains of patients with classical PKU in whom catecholamine production is diminished. One wonders what the mechanism might be that accounts for diminished catecholamine production in classical PKU, because the link to high Phe concentrations is not convincing.
Finally, all studies demonstrating functional effects of Tyr-related changes in catecholamine production have been pharmacologic. A physiological function has yet to be demonstrated for this relation. The most attractive candidate is chronic protein ingestion and selection, because Tyr concentrations and catecholamine synthesis vary directly with protein intake over a range of intakes that brackets the animal's protein requirement. Hence, the hypothesis is that through Tyr-driven changes in catecholamine production/release, the brain can monitor adequacy of protein intake and adjust protein-seeking behavior when these biochemical indices of protein intake fall below requirement values. However, an examination of this putative chemical-functional linkage appears presently to be impossible in the laboratory in rats or primates, because these animals willingly ingest levels of protein vastly in excess of their requirement (57) when in captivity, something they do not do in their native environments. It is currently unknown why laboratory animals willingly consume such high levels of protein in their diets, particularly because essential amino acids are metabolized, once ingested, when protein intake exceeds requirements (i.e. there is no obvious metabolic benefit) (58). Either an appropriate study needs to be designed that can be conducted in animals in their natural habitats or the explanation found and corrected regarding the abnormality of the environment in which laboratory animals are placed that leads to such unphysiologic protein-seeking behavior.
|
FOOTNOTES |
|---|
2 Author disclosures: J. D. Fernstrom received reimbursement from the conference sponsor for travel to the conference; he has a consulting agreement with the Ajinomoto Company, Inc. M.H. Fernstrom has a consulting agreement with the Ajinomoto Company, Inc.
3 Supported by the NIH (HD24730).
8 Abbreviations used: BBB, blood-brain barrier; DA, dopamine; DOPA, dihydroxyphenylalanine; LNAA, large, neutral amino acid; NE, norepinephrine; Phe, phenylalanine; PKU, phenylketonuria; TH, tyrosine hydroxylase; Tyr, tyrosine.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTLITERATURE CITED |
|---|
1. Fernstrom JD. Aromatic amino acids and monoamine synthesis in the central nervous system: influence of the diet. J Nutr Biochem. 1990;1:508–17.[Medline]
2. Fernstrom JD. Role of precursor availability in the control of monoamine biosynthesis in brain. Physiol Rev. 1983;63:484–546.
3. Kaufman S, Kaufman EE. Tyrosine hydroxylase. In: Blakley RL, Benkovic SJ, editors. Folates and pterins. 2nd vol. Chemistry and biochemistry of the pterins. New York: John Wiley and Sons; 1985. p. 251–352.
4. Nagatsu T, Levitt M, Udenfriend S. Tyrosine hydroxylase: the initial step in norepinephrine biosynthesis. J Biol Chem. 1964;239:2910–7.
5. Spector S, Gordon R, Sjoerdsma A, Udenfriend S. End-product inhibition of tyrosine hydroxylase as a possible mechanism for regulation of norepinephrine synthesis. Mol Pharmacol. 1967;3:549–55.
6. Iuvone PM, Rauch AL, Marshburn PB, Glass DB, Neff NH. Activation of retinal tyrosine hydroxylase in vitro by cyclic AMP-dependent protein kinase: characterization and comparison to activation in vivo by photic stimulation. J Neurochem. 1982;39:1632–40.[Medline]
7. Wurtman RJ, Larin F, Mostafapour S, Fernstrom JD. Brain catechol synthesis: control by train tyrosine concentration. Science. 1974;185:183–4.
8. Scally MC, Ulus I, Wurtman RJ. Brain tyrosine level controls striatal dopamine synthesis in haloperidol-treated rats. J Neural Transm. 1977;41:1–6.[Medline]
9. Iuvone PM, Galli CL, Garrison-Gund CK, Neff NH. Light stimulates tyrosine hydroxylase activity and dopamine synthesis in retinal amacrine neurons. Science. 1978;202:901–2.
10. Fernstrom MH, Volk EA, Fernstrom JD, Iuvone PM. Effect of tyrosine administration on dopa accumulation in light- and dark-adapted retinas from normal and diabetic rats. Life Sci. 1986;39:2049–57.[Medline]
11. Carlsson A, Davis JN, Kehr W, Lindqvist M, Atack CV. Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brain in vivo using an inhibitor of the aromatic amino acid decarboxylase. Naunyn-Schmiedebergs Arch Pharmacol. 1972;275:153–68.[Medline]
12. Carlsson A, Lindqvist M. Dependence of 5-HT and catecholamine synthesis on concentrations of precursor amino acids in rat brain. Naunyn-Schmiedebergs Arch Pharmacol. 1978;303:157–64.[Medline]
13. Fernstrom JD, Faller DV. Neutral amino acids in the brain: changes in response to food ingestion. J Neurochem. 1978;30:1531–8.[Medline]
14. Fernstrom MH, Volk EA, Fernstrom JD. In vivo inhibition of tyrosine uptake into rat retina by large neutral but not acidic amino acids. Am J Physiol. 1986;251:E393–9.[Medline]
15. Fernstrom MH, Fernstrom JD. Protein consumption increases tyrosine concentration and in vivo tyrosine hydroxylation rate in the light-adapted rat retina. Brain Res. 1987;401:392–6.[Medline]
16. Peters JC, Harper AE. Adaptation of rats to diets containing different levels of protein: effects on food intake, plasma and brain amino acid concentrations and brain neurotransmitter metabolism. J Nutr. 1985;115:382–98.
17. Gustafson JM, Dodds SJ, Burgus RC, Mercer LP. Prediction of brain and serum free amino acid profiles in rats fed graded levels of protein. J Nutr. 1986;116:1667–81.
18. Fernstrom MH, Fernstrom JD. Effect of chronic protein ingestion on rat central nervous system tyrosine levels and in vivo tyrosine hydroxylation rate. Brain Res. 1995;672:97–103.[Medline]
19. During MJ, Acworth IN, Wurtman RJ. Effects of systemic tyrosine on dopamine release from rat corpus striatum and nucleus accumbens. Brain Res. 1988;452:378–80.[Medline]
20. McTavish SFB, Cowen PJ, Sharp T. Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release. Psychopharmacology (Berl). 1999;141:182–8.[Medline]
21. Gibson CJ. Dietary control of retinal dopamine synthesis. Brain Res. 1986;382:195–8.[Medline]
22. Sugrue MF. Neuropharmacology of drugs affecting food intake. Pharmacol Ther. 1987;32:145–82.[Medline]
23. Subcommittee on Laboratory Animal Nutrition, NRC. Nutrient requirements of the laboratory rat. Nutrient requirements of laboratory animals. 4th revised ed. Washington: National Academy of Sciences; 1995. p. 11–79.
24. Nakagawa N. Bioenergetics of Japanese monkeys (Macaca fuscata) on Kinkazan island during winter. Primates. 1989;30:441–60.
25. Fernstrom JD, Fernstrom MH. Monoamines and protein intake: are control mechanisms designed to monitor a threshold intake or a set point? Nutr Rev. 2001;59:S60–5.[Medline]
26. Ikeda M, Levitt M, Udenfriend S. Hydroxylation of phenylalanine by purified preparations of adrenal and brain tyrosine hydroxylase. Biochem Biophys Res Commun. 1965;18:482–8.[Medline]
27. Shiman R, Akino M, Kaufman S. Solubilization and partial purification of tyrosine hydroxylase from bovine adrenal medulla. J Biol Chem. 1971;246:1330–40.
28. Abita JP, Dorche C, Kaufman S. Further studies on the nature of phenylalanine hydroxylation in brain. Pediatr Res. 1974;8:714–7.[Medline]
29. Karobath M, Baldessarini RJ. Formation of catechol compounds from phenylalanine and tyrosine with isolated nerve endings. Nat New Biol. 1972;236:206–8.[Medline]
30. Kapatos G, Zigmond MJ. Dopamine biosynthesis from L-tyrosine and L-phenylalanine in rat brain synaptosomes: preferential use of newly accumulated precursors. J Neurochem. 1977;28:1109–19.[Medline]
31. Katz I, Lloyd T, Kaufman S. Studies on phenylalanine and tyrosine hydroxylation by rat brain tyrosine hydroxylase. Biochim Biophys Acta. 1976;445:567–78.[Medline]
32. Fernstrom MH, Baker RL, Fernstrom JD. In vivo tyrosine hydroxylation rate in retina: effects of phenylalanine and tyrosine administration in rats pretreated with p-chlorophenylalanine. Brain Res. 1989;499:291–8.[Medline]
33. Greene LA, Tischler AS. PC12 pheochromocytoma cultures in neurobiological research. Adv Cell Neurobiol. 1982;3:373–414.
34. Ribeiro P, Pigeon D, Kaufman S. The hydroxylation of phenylalanine and tyrosine by tyrosine hydroxylase from cultured pheochromocytoma cells. J Biol Chem. 1991;266:16207–11.
35. DePietro FR, Fernstrom JD. The relative roles of phenylalanine and tyrosine as substrates for DOPA synthesis in PC12 cells. Brain Res. 1999;831:72–84.[Medline]
36. Moats RA, Moseley KD, Koch R, Nelson M Jr. Brain phenylalanine concentrations in phenylketonuria: research and treatment of adults. Pediatrics. 2003;112:1575–9.
37. Sved AF, Fernstrom JD, Wurtman RJ. Tyrosine administration reduces blood pressure and enhances brain norepinephrine release in spontaneously hypertensive rats. Proc Natl Acad Sci USA. 1979;76:3511–4.
38. Sved AF, Fernstrom JD, Wurtman RJ. Tyrosine administration decreases serum prolactin levels in chronically reserpinized rats. Life Sci. 1979;25:1293–9.[Medline]
39. Shurtleff D, Thomas JR, Schrot J, Kowalski K, Harford R. Tyrosine reverses a cold-induced working memory deficit in humans. Pharmacol Biochem Behav. 1994;47:935–41.[Medline]
40. Yeghiayan SK, Luo S, Shukitt-Hale B, Lieberman HR. Tyrosine improves behavioral and neurochemical deficits caused by cold exposure. Physiol Behav. 2001;72:311–6.[Medline]
41. Gelenberg AJ, Wojcik JD, Falk WE, Baldessarini RJ, Zeisel SH, Schoenfeld D, Mok GS. Tyrosine for depression: a double-blind trial. J Affect Disord. 1990;19:125–32.[Medline]
42. During MJ, Acworth IN, Wurtman RJ. Dopamine release in rat striatum: physiological coupling to tyrosine supply. J Neurochem. 1989;52:1449–54.[Medline]
43. Pardridge WM. Brain metabolism: a perspective from the blood-brain barrier. Physiol Rev. 1983;63:1481–535.
44. Biggio G, Porceddu ML, Gessa GL. Decrease of homovanillic, dihydroxyphenylacetic acid and cyclic-adenosine-3',5'-monophosphate content in the rat caudate nucleus induced by the acute administration of an amino acid mixture lacking tyrosine and phenylalanine. J Neurochem. 1976;26:1253–5.[Medline]
45. Fernstrom MH, Fernstrom JD. Acute tyrosine depletion reduces tyrosine hydroxylation rate in rat central nervous system. Life Sci. 1995;57:PL97–102.[Medline]
46. Montgomery AJ, McTavish SF, Cowen PJ, Grasby PM. Reduction of brain dopamine concentration with dietary tyrosine plus phenylalanine depletion: an [11C]raclopride PET study. Am J Psychiatry. 2003;160:1887–9.
47. Jaskiw GE, Kirkbride B, Bongiovanni R. In rats chronically treated with clozapine, tyrosine depletion attenuates the clozapine-induced in vivo increase in prefrontal cortex dopamine and norepinephrine levels. Psychopharmacology (Berl). 2006;185:416–22.[Medline]
48. McTavish SFB, Raumann B, Cowen PJ, Sharp T. Tyrosine depletion attenuates the behavioural stimulant effects of amphetamine and cocaine in rats. Eur J Pharmacol. 2001;424:115–9.[Medline]
49. Harmer CJ, McTavish SFB, Clark L, Goodwin GM, Cowen PJ. Tyrosine depletion attenuates dopamine function in healthy volunteers. Psychopharmacology (Berl). 2001;154:105–11.[Medline]
50. McTavish SFB, McPherson MH, Sharp T, Cowen PJ. Attenuation of some subjective effects of amphetamine following tyrosine depletion. J Psychopharmacol. 1999;13:144–7.
51. McTavish SF, McPherson MH, Harmer CJ, Clark L, Sharp T, Goodwin GM, Cowen PJ. Antidopaminergic effects of dietary tyrosine depletion in healthy subjects and patients with manic illness. Br J Psychiatry. 2001;179:356–60.
52. Leyton M, Young SN, Pihl RO, Etezadi S, Lauze C, Blier P, Baker GB, Benkelfat C. Effects on mood of acute phenylalanine/tyrosine depletion in healthy women. Neuropsychopharmacology. 2000;22:52–63.[Medline]
53. McLean A, Rubinsztein JS, Robbins TW, Sahakian BJ. The effects of tyrosine depletion in normal healthy volunteers: implications for unipolar depression. Psychopharmacology (Berl). 2004;171:286–97.[Medline]
54. Iuvone PM, Galli CL, Neff NH. Retinal tyrosine hydroxylase: comparison of short-term and long-term stimulation by light. Mol Pharmacol. 1978;14:1212–9.
55. Westerink BHC, Wirix E. On the significance of tyrosine for the synthesis and catabolism of dopamine in rat brain: evaluation by HPLC with electrochemical detection. J Neurochem. 1983;40:758–64.[Medline]
56. Milner JD, Irie K, Wurtman RJ. Effects of phenylalanine on the release of endogenous dopamine from rat striatal slices. J Neurochem. 1986;47:1444–8.[Medline]
57. Ashley DV, Anderson GH. Food intake regulation in the weanling rat: effects of the most limiting essential amino acids of gluten, casein, and zein on the self-selection of protein and energy. J Nutr. 1975;105:1405–11.
58. Tanaka H, Nakatomi Y, Takahashi K, Ogura M. Metabolism of lysine and tryptophan in growing rats at various dietary protein levels. Agric Biol Chem. 1991;55:531–7.
59. Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005;135:S1539–46.
This article has been cited by other articles:
|
|
 |
|
  K. Takai Introduction to the Transdisciplinary International Conference on Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application J. Nutr., June 1, 2007; 137(6): 1501S - 1503S. [Full Text] [PDF]
|
|
|
|
|
|
Y. Shimomura and S. M. Morris Jr. Biology and Biochemistry: Discussion of Session 2 J. Nutr., June 1, 2007; 137(6): 1548S - 1548S. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
