BEHAVIOURAL EFFECTS OF NUTRIENTS

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Nutrition: The

Changing Scene

BEHAVIOURAL EFFECTS OF NUTRIENTS RICHARD J. WURTMAN

Laboratory of Neuroendocrine Regulation, Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA MOST drugs that modify normal or abnormal behaviours do so by changing the amounts of particular neurotransmitters present within brain synapses or by influencing the interactions between transmitter molecules and their postsynaptic receptors. If a food constituent can be shown to cause similar changes in the release or the actions of one of these neurotransmitters, there is every reason to expect that that nutrient will also be able to influence behaviour (or to modify other processes controlled by the brain, such as neuroendocrine secretion and various autonomic functions). Certain food constituents do affect the rates at which neurons synthesise and release the neurotransmitters produced from them. One such nutrient, tryptophan, can readily be shown to affect behaviours. In our studyl of young healthy men who ingested a single dose of tryptophan, tyrosine, or the relevant placebo in the morning tryptophan significantly increased self-reported fatigue/intertia and reduced vigour/activity (fig 1). Other nutrients, particularly tyrosine and choline, can be used like drugs to enhance the release of their neurotransmitter products in disease states or during periods of sustained neuronal activity. I aim to summarise here the effects of these nutrients-consumed in pure form or as constituents of foods-on brain composition, the involvement of this process in normal behaviours such as appetite control, and the rationale underlying the use of neurotransmitter precursors in treating neurological diseases. PRECURSOR CONTROL OF NEUROTRANSMITTER SYNTHESIS

Serotonin The synthesis of serotonin, 5-hydroxytryptamine (5-HT), in neurons is initiated by the hydroxylation of the essential aminoacid tryptophan. The enzyme that catalyses this reaction, tryptophan hydroxylase, has a poor affinity for its aminoacid substrate; hence treatments that raise or lower brain tryptophan levels can, by changing the enzyme’s substrate saturation, rapidly alter the rate at which the and its tryptophan is hydroxylated product is to converted serotonin.2 Brain (5-hydroxytryptophan) in levels rats human and, probably, tryptophan beings, normally undergo pronounced variations when plasma aminoacid patterns change, for example, when foods are being digested and absorbed. A high-carbohydrate, proteinpoor meal elevates brain tryptophan, accelerating serotonin synthesis; in contrast, a high-protein meal depresses serotonin synthesis.’ The plasma parameter that couples food composition to brain tryptophan level is the ratio of the plasma tryptophan concentration to the summed concentrations of such other large neutral aminoacids (LNAA) as tyrosine, phenylalanine, and the branched-chain aminoacids leucine, isoleucine, and valine. 4-7 This parameter is important because the transport macromolecules within the capillary endothelia comprising the blood-brain barrier that carry circulating tryptophan into the brain also transport

Fig l-Effects of tryptophan, tyrosine, and their placebos mood scales of the profile of mood states (POMS).

on

the six

the other LNAA with almost equal efficiency, so circulating tryptophan must compete with the other LNAA for transport sites.8 A carbohydrate-rich meal raises the plasma tryptophan ratio9 by eliciting the secretion of insulin, which has little effect on plasma tryptophan but greatly lowers plasma levels of the other LNAA, largely by facilitating their uptake into skeletal muscle (fig 2). A protein-rich meal depresses the ratio9 by contributing very large quantities of the branchedchain aminoacids to the systemic circulation, but only small amounts of tryptophan (which is the least abundant aminoacid in proteins and also is destroyed in the liver). This coupling of food composition to serotonin release allows serotoninergic neurons to function as variable ratio sensors, informing the rest of the brain about the proportions of protein and carbohydrate in the most recent meal. The brain can then use this information in deciding what to eat at the next meal. Serotonin release from brain neurons can also be increased by ingesting pure tryptophan, especially together with an insulin-releasing carbohydrate (to lower the levels of the other plasma LNAA, thereby facilitating tryptophan’s

Fig 2-Diurnal variations in plasma tryptophan levels and the plasma tryptophan ratio in young men consuming test diets containing 0 g, 75 g, or 150 g protein/day for five consecutive days each.

Plasma tryptophan levels rose in proportion to protem intake, but plasma tryptophan ratio fell. The "normal range" for this ratio in people consuming meals containing 0-50 g protein is thus about twofold.

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uptake into the brain 10). Conversely, serotonin release can be depressed by ingesting large doses of any other LNAA, including both the aminoacids present in protein and

synthetic compounds, such as L-dopa or alpha-methyldopa, used therapeutically. Tryptophan’s efficacy-and that of any other natural or synthetic LNAA"-is diminished if it is consumed along with protein; the LNAA in the protein suppress its uptake into the brain. Catecholamines and Acetylcholine The rates at which the enzymes tyrosine hydroxylase and choline acetyltransferase convert tyrosine to dopa 12, 13and choline to acetylcholine,14,15 respectively, can similarly be modulated by treatments that change brain levels of tyrosine or choline. Brain tyrosine levels are most conveniently increased by ingesting pure tyrosine, alone or with a carbohydrate (to lower plasma levels of the competing LNAA). Consumption of a high-protein meal also increases the plasma tyrosine ratio and brain tyrosine levels slightly, but probably not enough to have major effects on catecholamine synthesis. Brain choline levels are increased by consumption of pure choline or of phosphatidylcholine 16 (lecithin), the substance providing most of the choline in the diet. Choline uptake into the brain is also catalysed by a transport macromolecule within the endothelia of brain capillaries;8 apparently choline is the only major circulating ligand for this transport mechanism. Under basal when a conditions, particular or neuron is not firing catecholaminergic cholinergic frequently, it will respond poorly if at all to an increase in available tyrosine",’or choline.19 However, when the neurons become physiologically active, they concurrently become highly responsive to increases in precursor levels, synthesising and releasing more dopamine, for example, when brain tyrosine levels are raised, 1,2’ and more acetylcholine after choline21 or lecithin 12 is eaten. The biochemical mechanism that couples neuronal firing frequency to tyrosine-responsiveness apparently involves the activation (by phosphorylation) of tyrosine hydroxylase; this process greatly increases the enzyme’s affinity for, and saturation with, its tetrahydrobiopterin co-factor,23 causing its activity to become limited by the extent to which it is saturated with its aminoacid substrate, tyrosine. Phosphorylation of the enzyme also diminishes its sensitivity to end-product inhibition by catecholamines, further increasing the rate at which the neuron converts tyrosine to dopamine or noradrenaline. The biochemical mechanism that couples a cholinergic neuron’s firing frequency to its ability to synthesise more acetylcholine when given more choline remains unknown. The dependence of catecholaminergic and cholinergic neurons on sustained physiological activity for precursorresponsiveness (which is not observed in serotoninergic neurons2‘’) imparts considerable specificity to the functional consequences of giving patients tyrosine or choline: the brain apparently can choose which particular catecholaminergic or cholinergic neurons will be allowed to respond to having more precursor, simply by doing what it normally does-modulating the firing frequencies of the neurons. This ability probably explains the paucity of side-effects observed in people given even very large doses of tyrosine25,26 or of choline-containing compounds.27,28it also explains why a particular dose of tyrosine can be used either to reduce blood pressure in hypertension29 (by enhancing noradrenaline release from brainstem noradrenergic neurons that reduce

sympathetic outflow) or to raise blood pressure in haemorrhagic shock J() (by increasing catecholamine secretion from the physiologically active sympathoadrenal cells). Attempts to use tyrosine or choline-containing compounds to treat diseases of catecholamine or acetylcholine deficiency are in their infancy. Progress has been retarded by the unusual regulatory status of these compounds (foods or drugs?) and by the unavailability until recently of pure and palatable lecithin preparations. Tyrosine has been reported to help some patients with depression31 or mild Parkinson’s disease.26 Choline or lecithin have been used successfully to treat tardive dyskinesia, 27,32,33 mania,34 and ataxias.28 Administration of choline or lecithin alone for short periods has not led to reproducible improvement in patients with advanced Alzheimer’s disease;35 however, current attempts in which the precursor is given with physostigmine36 or piracetam, or is given alone for long periods may meet with more success.

BRAIN SEROTONIN AND THE CONTROL OF APPETITE

If animals

are

allowed

a

choice of

two or more

diets

(unfortunately an unusual circumstance in most research on appetite control) each containing different proportions of carbohydrates or protein or both, they are able to regulate not only the total quantities of food and of calories that they consume, but also the proportions of protein" and carbohydrates. 38 Administration ofasmall carbohydrate-rich pre-meal before exposure to the test diets39 or administration of drugs (eg, fenfluramine or fluoxetiner°) that enhance serotonin’s release or suppress its inactivation causes the animal to adjust its food choices so as to increase the proportion of protein to carbohydrate in the total meal. Similar observations have been made in people given fenfluramine (or, to a lesser extent, tryptophan) and allowed to choose among snacks41 or meal constituents (fig 3)

Fig 3-Effect of fenfluramine (15 mg by mouth twice daily) or its placebo on the proportion of total daily calories consumed as carbohydrates by thirteen moderately obese carbohydrate-craving adult inpatients at a clinical research centre. Subjects could choose as many portions as they wanted from six different

isocaloric items at breakfast, lunch, and dinner and from ten isocaloric snack foods, available continuously m a vending machine. Dotted hnes indicate those who did

not

reduce total calone intake

on

this

drug dose.

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containing varying proportions of protein and carbohydrate. In the study shown in fig 3 all those who responded to fenfluramine by reducing total calorie intake also

significantly decreased the proportion of calorie intake supplied by carbohydrate, and increased the proportion supplied by protein, whereas fat consumption was not significantly affected. Most of the fall in carbohydrate intake related to reduction of snack-food intake (J. J. Wurtman, unpublished). These observations imply that the brain was

mechanisms regulating protein and carbohydrate appetites The brain carbohydrate-rich, protein-poor meal, by increasing serotonin levels, reduces the likelihood that the next meal will be of similar composition. Conversely, consumption of carbohydrate-poor, protein-rich meals (like those widely used for weight reduction) diminishes brain serotonin synthesis, thus increasing the subject’s desire for carbohydrate, often to the point of carbohydrate-craving.42 Prolonged consumption of such meals may exacerbate the neurochemical and appetitive changes by diminishing the quantities of insulin secreted after meals: this would be expected to increase plasma levels of the competing branched-chain LNAA (unpublished). The insulin-resistance of obesity might be expected to have a similar effect on the plasma aminoacid pattern and brain serotonin levels. We observe that a sizeable proportion of obese subjects seeking assistance in weight reduction consume as much as half of their total daily intake as carbohydrate-rich snacks and that this behaviour is often associated with strong feelings of carbohydrate craving. Conceivably this appetite disorder reflects an abnormality in the processes that couple carbohydrate consumption to the release of brain serotonin. The carbohydrate-snack eating can be effectively controlled by small doses of a serotonin-releasing agent (fig 3). Many patients describe themselves as feeling anxious, tense, or depressed before consuming the carbohydrate snack and peaceful or relaxed afterwards. It may be more than a coincidence that dietary carbohydrates and both major classes of antidepressant drugs, the monoamine-oxidase inhibitors and the tricyclic-uptake blockers, are thought to increase the quantities of serotonin present within brain synapses. Carbohydrate consumption or tryptophan administration can also modulate other normal behaviours, increasing subjective fatigue (fig 1) and sleepiness, accelerating sleep onset in people with prolonged sleep latencies,43 diminishing sensitivity to mild pain, and (in people over 40) increasing the likelihood of errors in performance tests.44 At present no information is available on the relative potencies of sugars and starches in producing such effects. It might be expected that a carbohydrate’s potency would depend upon its speed of absorption and its ability to stimulate insulin secretion. I hope that future studies on the behavioural effects of food constituents will, in their formulation, take full advantage of the growing body of knowledge about the neurochemical effects of nutrients, and, in their implementation, include biochemical studies to affirm that the food-induced changes in plasma composition needed to mediate the brain’s responses do indeed occur.

involve, among others, serotonin-releasing

neurons.

’

REFERENCES

1 Lieberman HR, Corkin S, Spring BJ, Growdon JH, Wurtman RJ Mood and sensorimotor performance after neurotransmitter precursor administration. Soc Neurosci (abstr) 1982; 8: 395.

2 Fernstrom JD, Wurtman RJ Brain serotonin content: physiological dependence plasma tryptophan levels. Science 1971; 173: 149-52.

on

JD, Wurtman RJ Brain serotonin content. increase following ingestion of carbohydrate diet Science 1971; 174: 1023-25 Fernstrom JD, Wurtman RJ. Brain serotonin content, physiological regulation by plasma neutral amino acids Science 1972, 178: 414-16. Fernstrom JD, Wurtman RJ. Nutrition and the brain. Sci Am 1974; 230: 84-91. Wurtman RJ. Nutrients that modify brain function. Sci Am 1982; 246: 42-51. Wurtman RJ, Hefti F, Melamed E. Precursor control of neurotransmitter synthesis.

3 Fernstrom 4 5.

6 7.

Pharmacol Rev 1980; 32: 315-35. WM Regulation of amino acid availability to the brain. In: Wurtman RJ, Wurtman JJ, eds. Nutrition and the brain New York Raven Press, 1977. 141-204. 9 Fernstrom JD, Wurtman RJ, Hammerstron-Wiklund B, Rand WM, Munro HN, Davidson CS. Diurnal variations in plasma concentrations of tryptophan, tyrosine, and other neutral amino acids effect of dietary protein intake. Am J Clin Nutr 1979; 32: 1912-22 10 Martin-Du Pan R, Mauron C, Glaeser B, Wurtman RJ Effect of increasing oral glucose doses on plasma neutral amino acid levels. Metabolism 1982; 41: 937-43 11. Markovitz DC, Fernstrom JD Diet and uptake of aldomet by the brain. competition with natural large neutral amino acids Science 1977; 197: 1014-15. 12 Wurtman RJ, Larin F, Mostafapour S, Fernstrom JD Brain catechol synthesis control by brain tyrosine concentration. Science 1974; 185: 183-84. 13 Carlsson A, Lindqvist M. Dependence of 5-HT and catecholamine synthesis on concentrations of precursor amino-acids in rat brain. Naunyn-Schmiedeberg Arch Pharmacol 1978, 303: 157-64. 14. Cohen EL, Wurtman RJ. Brain acetylcholine: increase after systemic choline administration. Life Sci 1975, 16: 1095-1102. 15. Haubrich DR, Wang PFL, Clody DE, Wedeking PW. Increase in rat brain acetylcholine induced by choline or deanol Life Sci 1975; 17: 975-80 16. Hirsch MJ, Wurtman RJ. Lecithin consumption increases acetylcholine concentrations in rat brain and adrenal gland. Science 1978, 202: 223-25. 17 Scally MC, Ulus I, Wurtman RJ. Brain tyrosine level controls striatal dopamine synthesis in haloperidol-treated rats. J Neurol Transm 1977; 41: 1-6 18 Fuller RW, Snoddy HD. L-tyrosine enhancement of the elevation of 3, 4-dihydroxyphenylacetic acid concentration in rat brain by spiperone and mafonelic acid. J Pharm Pharmacol 1982; 34: 117-18. 19. Bierkamper GG, Goldberg AM Release of acetylcholine from the vascular perfused rat phrenic nerve-hemidiaphragm Brain Res 1980; 202: 234-37. 20 Melamid E, Hefti F, Wurtman RJ Tyrosine administration increases striatal dopamine release in rats with partial nigrostriatal lesions Proc Natl Acad Sci USA 8

Partridge

1980; 77: 4305-09 Wecker L, Dettbarn W-D, Schmidt D. Choline administration· modification of central actions of atropine Science 1977; 199: 86-87. 22. Wurtman RJ, Hirsch MJ, Growdon J. Lecithin consumption raises serum free choline levels. Lancet 1977; ii: 68-69. 23. Levine RA, Miller LP, Lovenberg W. Tetrahydrobiopterin in striatum: localization in dopamine nerve terminals and role in catecholamine synthesis. Science 1981, 214: 21.

919-21. Colmenares JL, Wurtman RJ. Failure of decreased serotonin uptake or monoamine oxidase inhibition to block the acceleration in brain 5-hydroxyindole synthesis that follows food consumption. J Neural Transm 1975; 37: 15-32 25 Melamed E, Glaeser B, Growdon JH, Wurtman RJ. Plasma tyrosine in normal humans: effects of oral tyrosine and protein-containing meals J Neural Transm 24

Jacoby J,

1980, 47: 299-306 JH, Melamed E, Logue M, Hefti F, Wurtman RJ Effects or oral L-tyrosine

26. Growdon

administration on CSF tyrosine and homovanillic acid levels in patients with Parkinson’s disease. Life Sci 1982; 30: 827-32. 27. Growdon JH, Hirsch MJ, Wurtman RJ, Wiener W Oral choline administration to patients with tardive dyskinesia N Engl J Med 1977; 297: 524-27. 28. Barbeau A, Growdon JH, Wurtman RJ, eds. Choline and lecithin in brain disorders Vol V, Wurtman RJ, Wurtman JJ, eds. Nutrition and the brain. New York Raven

Press, 1979 29. 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: 3511-14. 30. Conlay LA, Maher TJ, Wurtman RJ. Tyrosine increases blood pressure in hypotensive rats Science 1981; 212: 559-60. 31 Gelenberg AJ, Wurtman RJ L-tyrosine in depression Lancet 1980; ii: 863-64. 32. Davis KL, Berger PA, Hollister LE Choline for tardive dyskinesia. N Engl J Med 1975, 293: 152. 33. Growdon JH, Gelenberg AJ, Doller J, Hirsch MJ, Wurtman RJ Lecithin can suppress tardive dyskinesia. N Engl J Med 1978; 298: 1029-30 34 Cohen BM, Lipinski JF, Altesman RI Lecithin in the treatment of mama: doubleblind, placebo-controlled trials Am J Psychiatry 1982; 139: 1162-64. 35. Corkin S, Davis K, Growdon JH, Usdin E, Wurtman RJ, eds. Alzheimer’s disease a report of progress in research. New York Raven Press, 1982 36. Thal LJ, Fuld PA, Masur DM, Sharpless ND. Oral physostigmine and lecithin improve memory in Alzheimer’s disease. Ann Neurol (in press). 37 Ashley DVM, 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 38. Wurtman JJ, Wurtman RJ Drugs that enhance central serotoninergic transmission diminish elective carbohydrate consumption by rats Life Sci 1979, 24: 895-904. 39. Wurtman JJ, Moses PL, Wurtman RJ Prior carbohydrate consumption affects the amount of carbohydrate that rats choose to eat. J Nutr 1983; 113: 70-78 40 Wurtman JJ, Wurtman RJ. Fenfluramine and fluoxetine spare protein consumption while suppressing carbohydrate intake by rats. Science 1977; 198: 1178-80 41. Wurtman JJ, Wurtman RJ, Growdon JH, Henry P, Lipscomb A, Zeisel SH. Carbohydrate craving in obese people. suppression by treatments affecting J serotoninergic transmission Int Eating Disorders 1981; 1: 2-15 42. Wurtman JJ. The carbohydrate craver’s diet Boston Houghton-Mifflin, 1983 43. Hartmann E, Spinweber CL, Ware C. L-tryptophan, 1-leucine, and placebo: effects on subjective alertness Sleep Res 1976, 5: 57-66. 44. Spring B, Maller O, Wurtman J, Dingman L Effects of protein and carbohydrate meals on mood and performance. J Psychiatr Res (in press).