T HE R ELATIONSHIP BETWEEN C ARBOHYDRATES AND S EROTONIN

13.2.1 T HE R ELATIONSHIP BETWEEN C ARBOHYDRATES AND S EROTONIN

The biosynthesis of serotonin, 5-HT or 5-hydroxytryptamine, is accomplished by converting tryptophan to 5-hydroxytryptophan, 5-HTP, by the reaction of the enzyme tryptophan hydroxylase. 5-HTP is then converted to serotonin by the enzyme 5-HTP decarboxylase. Tryptophan is therefore necessary for the synthesis of 5-HT, and this amino acid must be obtained from the diet. If the diet contains little tryptophan, the precursor for synthesis of serotonin will not be available and the synthesis of serotonin will decline. This effect was clearly demonstrated by

Fernstom and Wurtman 18 in an experiment involving feeding rats a corn diet for

5 weeks. Because corn has very little tryptophan, the rats were deprived of it, resulting in a decline in plasma levels of tryptophan and brain levels of tryptophan and serotonin. Similarly, increasing the availability of tryptophan in the diet should result in increased plasma tryptophan levels and brain levels of tryptophan and

serotonin. This is exactly what has been found in both rats 18 and humans. 19 A sixfold elevation in cortical tryptophan levels was revealed in excised brain tissue obtained from neurological patients following infusion of tryptophan. 19 Addition- ally, cerebral spinal fluid 5-HIAA (the principal metabolite of serotonin) has been shown to increase following a tryptophan load. 20

While it is quite logical that increasing the dietary intake of tryptophan should increase plasma and brain tryptophan levels and, consequently, the synthesis of

Functional Food Carbohydrates

central serotonin, it is counterintuitive to think that consumption of a carbohydrate- rich meal would have a similar effect, because such a meal contains little, if any, tryptophan. However, this is exactly what Wurtman and his colleagues identified. Interest in the effect of a meal composed of a single nutrient on brain serotonin levels was prompted by studies indicating that both insulin and a carbohydrate meal have little effect on plasma tryptophan but decreased all other amino acids. 21,22 Additionally, both insulin and the carbohydrate meal increased brain tryptophan

and serotonin levels. 21 This meant that insulin, whether administered exogenously or secreted endogenously, resulted in an increase in both plasma tryptophan and brain tryptophan and serotonin levels. Subsequent research 23 revealed that plasma tryptophan has the characteristic of loosely binding to circulating albumin. When insulin is secreted, nonesterified fatty acid molecules, which are typically bound to albumin, dissociate themselves and enter adipocytes. This dissociation permits tryptophan to be loosely bound to albumin and protects it from being taken up by peripheral cells. The net effect is that there is little change in total plasma tryp- tophan levels following insulin secretion, although the plasma levels of many of the other amino acids decrease.

The sparing of tryptophan from being taken up by peripheral cells is important because the system by which tryptophan is transported across the blood–brain barrier is competitive because it also transports the other large neutral amino acids. 24 Because it is competitive, anything that increases the plasma level of tryptophan relative to the other large neutral amino acids would increase the amount of tryp- tophan transported into the brain. Because a carbohydrate-rich and protein-poor meal has, by definition, little protein, consumption of such a meal would preclude a rise in plasma levels of amino acids. However, the carbohydrate component would stimulate the secretion of insulin, which would cause an uptake of plasma amino acids by peripheral cells. It would also cause nonesterified fatty acid molecules to enter adipocytes, leaving albumin in an unbound state. The unbound albumin would bind loosely to tryptophan, sparing it from entering peripheral cells. This would increase the ratio of plasma tryptophan to the other large neutral amino acids and increase the amount of tryptophan that enters the brain’s extracellular space. There would therefore be more of the precursor of serotonin available for synthesis, leading to an increased synthesis of central serotonin. Because the enzyme catalyzing the hydroxylation of tryptophan to 5-HTP is only half saturated with its substrate, 24 increasing the availability of tryptophan should increase the synthesis of 5-HT. It has been well established that increasing brain tryptophan levels increases the level of brain serotonin as well as its major metabolite, 5-hydroxyindoleacetic acid. 12

This demonstrated effect of consumption of a carbohydrate-rich, protein-poor meal on the synthesis of central serotonin has been the driving force behind a large portion of the research investigating the mood- and performance-altering effects of carbohydrates. It is also one of the most frequently used explanations for a demon- strated behavioral effect following the consumption of a carbohydrate-rich and protein-poor meal. There are, however, a number of serious limitations surrounding the use of this idea as an explanation for a carbohydrate-mediated effect on behavior.

Teff et al. 25 demonstrated that in humans, meals containing as little as 4% protein could counteract a carbohydrate-induced rise in the plasma tryptophan ratio. In rats,

Dietary Carbohydrates as Mood and Performance Modulators

the protein content of a meal has to exceed 6% to negate a carbohydrate-induced rise in brain tryptophan level. 26 This is a significant finding because it is difficult to consume a meal or even a carbohydrate snack that contains less than 4% protein. Therefore, unless a person consumes pure sucrose or glucose, sufficient protein would be consumed to negate a rise in the ratio of tryptophan to the other large neutral amino acids (LNAAs), the essential requirement for a rise in brain tryptophan levels, and an increase in the synthesis of central serotonin. Even if a meal or snack contained such a small amount of protein that a rise in the tryptophan/LNAA ratio did occur, the evidence suggests that the rise would be so small as to have little effect on central serotonin. Apparently the plasma tryptophan/LNAA ratio must rise at least 50 to 100% to produce a change in brain 5-HT synthesis. 27,28

A rise of that magnitude does not occur even when a pure carbohydrate, such as glucose, is administered. 29 Most studies have found a rise in the tryptophan/LNAA ratio of <25%, and only one study 25 found a rise as high as 47%, which still does not meet the criteria of a 50 to 100% rise needed to increase the synthesis of central serotonin. Fernstrom 30 has appropriately pointed out that an animal must fast prior to consuming a carbohydrate-rich and protein-poor meal to elevate the plasma tryp- tophan/LNAA ratio sufficiently to stimulate serotonin synthesis. However, humans

eat, on average, five to seven times a day. 31 This means that humans seldom meet the criteria of fasting prior to consuming a meal regardless of its composition. Rather,

the frequency of consumption of food by humans suggests that the consumption of one meal or snack at one time influences the physiologic response to a subsequent

meal or snack. Fernstrom and Fernstrom 26 revealed that consumption of a carbohy- drate meal had no effect on brain tryptophan or 5-HTP levels if it was consumed 2

h after a meal containing 12% protein. Also, the physiologic effect of a carbohydrate meal on cortical and hypothalamic 5-HTP levels was reversed by the ingestion, 2 h later, of a meal containing a moderate amount of protein (12%).

Taken together, these results reveal that both a prior and a subsequent protein- containing meal can affect the physiologic response to a carbohydrate meal. If a 3-h intermeal interval existed, the physiologic effect of a meal was unaffected by either a subsequent or prior meal. However, this effect was observed in rats and the rate of metabolism in rats is greater than that which exists in humans. 32 Therefore, the intermeal interval would probably have to be longer than 3 h to avoid a sequential effect in humans. Because an intermeal interval longer than 3

h does not typically exist with humans, 31 and most meals and snacks comprise at least 10% protein, a carbohydrate-rich meal or snack would seem to have little effect on brain tryptophan levels or the synthesis of central serotonin. As Young 33 has stated, “At the moment the weight of the evidence indicates that it [the effect of a carbohydrate meal on synthesis of central serotonin] is not an important phenomenon in humans” (p. 900).

While the evidence seems to overwhelmingly suggest that any behavioral effect created by a carbohydrate-rich meal is not due to its effect on central serotonin function, this does not preclude an effect occurring under extreme physiologic or pathologic conditions that would lead to an increased use of central serotonin or to

the depletion of serotonin. 16 Under such conditions, a specific meal condition that alters the availability of a precursor may also alter neurotransmitter levels 34 and, as

a result, have a behavioral effect.

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