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,4
Departments of * Psychiatry, Pharmacology, ** Epidemiology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh PA 15213
4 To whom correspondence should be addressed. E-mail: fernstromjd{at}upmc.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • exercise • central fatigue • tryptophan • serotonin • brain
The fatigue that accompanies physical exercise is thought to derive from 1) metabolic changes in muscle that ultimately lead to muscle exhaustion and 2) modifications in the central nervous system (CNS)5 that diminish motor neuron impulse traffic to muscle. These latter changes are termed central fatigue (1). One current and widely held hypothesis of central fatigue is metabolic and posits that the increase in nonesterified fatty acid (NEFA) mobilization that accompanies exercise, and the resulting rise in serum NEFA concentrations, indirectly promote the entry of tryptophan (TRP) into the brain, increases brain TRP pools, and as a consequence, stimulates the synthesis and release of the neurotransmitter serotonin (5HT). Because increased 5HT release is associated with sleep and drowsiness, the notion is that such increases in 5HT promote central fatigue (2–5). This article analyzes the experimental basis for thinking that the exercise-induced rise in serum NEFA raises brain TRP, and as a consequence, stimulates neuronal 5HT synthesis and release. It further considers the possibility that the relation of exercise to brain TRP concentrations and 5HT synthesis and release might not be so simple because not all 5HT neurons are active during exercise, and are thus probably not TRP-responsive. And finally, this article comments on the available data linking 5HT neuronal function to physical activity in the context of the search for a link between 5HT neurons and central fatigue.
Exercise, serum NEFA levels, and brain TRP uptake
Almost 50 years ago, McMenamy and Oncley reported that TRP binds to albumin in blood (6). The free TRP pool in blood ranges between 5–50% of the total TRP pool, depending on the physiologic or pharmacologic conditions of the study [e.g., (7–11)]. NEFA also bind to albumin; this binding is competitive with TRP (12). The proportion of TRP in blood that associates with albumin is thus affected by changes in blood NEFA concentrations. Hence, as serum NEFA concentrations rise, NEFA molecules displace TRP molecules from albumin, and the proportion of TRP in blood circulating in the free form increases. The binding of molecules to serum proteins can retard their availability for tissue uptake (13); this notion facilitates the hypothesis that the free pool of TRP is the fraction of the amino acid available for brain uptake. Hence, because serum NEFA concentrations influence the binding of TRP to albumin, changes in serum NEFA should directly influence the free TRP pool, and thus brain TRP uptake and levels (7,14). The strongest evidence adduced in support of this hypothesis involved a number of treatments that were reported to increase serum (or plasma) NEFA, free TRP and brain TRP concentrations together (namely, immobilization stress, a 24-h period of starvation, or the administration of certain drugs) (7,14,17). [Note that both plasma and serum have been used to determine the free and albumin-bound fractions of TRP in blood. Provided heparin is not used in the preparation of plasma (it interferes with TRP binding to albumin (15,16) and EDTA is preferred), either plasma or serum is thought to provide valid estimates of the free and albumin-bound fractions of TRP. In this article, plasma and serum are both used, as appropriate to the research under discussion.]
Some years later, Chaouloff and associates observed that the rise in plasma NEFA caused by forced treadmill exercise in rats (20 m/min for 1 h) was also associated with an increase in plasma free TRP, but not total TRP concentrations, as well as increases in brain TRP concentrations and the principal 5HT metabolite, 5-hydroxyindoleacetic acid (5HIAA) (18,19). They interpreted their findings as indicating that exercise promoted a rise in brain 5HT synthesis, turnover, and release through a cascade of an exercise-induced increase in plasma NEFA concentrations that leads to a rise in plasma free (but not total) TRP concentrations, and thus brain TRP uptake and brain TRP concentrations. The increase in brain TRP concentrations could elicit a rise in 5HT synthesis, because the enzyme that catalyzes the initial and rate-limiting step in 5HT synthesis, TRP hydroxylase, is not fully saturated with substrate at normal brain TRP concentrations (20,21). Subsequently, Blomstrand, Newsholme, and associates embraced this free TRP model to explain exercise-induced increases in brain TRP, with modification to include effects related to the branched-chain amino acids [see Blomstrand (5)].
Because the free TRP model continues to be an accepted concept in the exercise community for explaining exercise-induced increases in brain TRP [e.g., see (2,5,22)], it is worth reviewing some of the evidence that makes the link between plasma free TRP and brain TRP, if only to inquire as to whether more (or less) might be going on than meets the eye.
The free TRP hypothesis, as it applies to exercise, surfaced some years after this issue had been exhaustively debated in the pharmacology and nutrition communities. Although not everyone agrees, the general outcome over time seems to be that the albumin binding of TRP in blood does not influence brain TRP uptake and levels to any appreciable extent. A few examples illustrate this point. First, at the time the hypothesis was originally put forth, it was already known that the ingestion of a carbohydrate meal by rats would rapidly raise brain TRP levels and stimulate 5HT synthesis, and that this effect was linked to insulin secretion (23). Because insulin reduces plasma NEFA concentrations, and thus could be expected to reduce the plasma free TRP pool, it was immediately clear that this paradigm would demonstrate a dissociation of the free TRP and brain TRP pools. Such, indeed, turned out to be the case (11,24). Second, additional studies followed that were based on an interesting nutritional/metabolic feature of rats (which does not hold for humans) that the ingestion of a fat-containing meal rapidly raises plasma NEFA concentrations; the effect is dose dependent. Hence, Madras et al. (25) studied the response of brain TRP soon after fasting rats consumed a meal containing 20% protein and one of several levels of fat (0, 15, 30, or 45%). They observed that as the fat content of the meal increased, serum NEFA concentrations and free TRP concentrations rose, and yet brain TRP concentrations did not (25). The interpretation offered was that circulating free TRP concentrations do not influence brain TRP uptake and levels. Of course, this study could be criticized, because the meals contained a sizeable amount of protein, which should increase blood concentrations of other large neutral amino acids (LNAAs) that compete with TRP for transport into the brain, sufficiently to retard blood–brain barrier (BBB) TRP uptake, regardless of the change in serum free TRP. Hence, the paradigm did not convincingly prove that free TRP had nothing to do with brain TRP uptake, just that any effects might be obscured by the presence of elevated concentrations of its LNAA competitors.
This objection was answered in a study in which any possible confusion introduced by changes in serum LNAA concentrations (other than TRP) was removed. The changes in serum LNAA concentrations following a meal occur primarily in response to the presence of protein in the meal (which raises blood levels of the LNAA, particularly the branched-chain amino acids), and to the secretion of insulin (which lowers blood LNAA levels). If meals are examined that lack protein (and have a variable fat content), and rats are studied that cannot secrete insulin (diabetic rats), then it should be possible to produce large changes in serum free TRP concentrations in response to such a meal, while holding the concentrations of all other LNAAs constant. If the free serum TRP pool is a determinant of brain TRP uptake and levels, this relation should clearly emerge in such a paradigm. Hence, overnight-fasted, streptozotocin diabetic rats ingested a carbohydrate meal containing either 0 or 45% fat (or remained fasting), and were examined 1, 2, or 3 h thereafter. Changes in serum were clearly evident 2 and 3 h after food presentation, and were similar. Representative data are presented in Table 1 (at 2 h). The 45% fat meal raised serum NEFA and produced a 2-fold rise in serum free TRP concentrations (compared with values in fasting rats or rats ingesting the 0% fat meal), and no changes in serum total TRP or the summed concentrations of the other LNAAs in serum (competitors for BBB transport). However, despite this large change in serum free TRP, TRP concentrations in the cerebral cortex and hypothalamus were not different among dietary treatment groups (Table 1). The same effect was seen 3 h after meal ingestion (26). These changes in serum NEFA and free TRP are as great as those seen following exercise in rats (4,18,19,27), and yet, unlike exercised animals, are associated with no changes in brain TRP concentrations.
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The absence of a change in brain TRP concentrations in rats, despite the large changes in serum free TRP concentrations elicited in a dietary study designed to eliminate confounding effects of LNAA variations (26), invites speculation as to whether the exercise-induced rise in brain TRP is caused by the increase in circulating free TRP concentrations. How might one assess whether the increase in brain TRP that occurs during exercise in rats follows from the increase in serum NEFA and serum free TRP concentrations? The easiest way would be to block, pharmacologically, the rise in serum NEFA, because this treatment should prevent the rise in serum free TRP, and thus brain TRP, if the latter depends on the former effect. Such an experiment was conducted by Chaouloff et al. (18), using nicotinic acid to prevent the exercise-induced rise in plasma NEFA concentrations in rats (they used plasma in their studies); nicotinic acid blocks activation of hormone-sensitive lipase (31). Nicotinic acid pretreatment completely blocked the rise in plasma NEFA (and free TRP) that occurs during exercise, but brain TRP concentrations still increased (see Table 2; the conclusion is the same, whether sedentary/nicotinic-acid and runner/nicotinic-acid groups are compared, or runner/saline and runner/nicotinic-acid groups are compared). The findings thus suggest that the running-induced rise in brain TRP does not require an increase in plasma free TRP concentration to occur. A similar conclusion can be drawn from a recent study in mice, in which nicotinic acid greatly attenuated the increases in plasma NEFA and free TRP, but not brain TRP concentrations that resulted from injection of a beta-3 adrenergic agonist (32). This finding is relevant to the present discussion, because the exercise-induced rise in plasma NEFA is caused by sympathetic activation (33). Nevertheless, to be certain of the conclusion, the exercise study should probably be repeated using a beta-adrenergic receptor antagonist, to make certain the result with nicotinic acid is seen using a different class of drug that also inhibits fatty acid mobilization during exercise (33). But, if the rise in brain TRP during exercise cannot be explained by an increase in serum free TRP, by what mechanism might exercise raise brain TRP concentrations? Something other than a reduction in serum LNAA concentrations would appear to be required, because there is disagreement as to whether exercise reduces the serum concentrations of these amino acids [e.g., see Chaouloff (22)]. Clearly, some interesting issues remain to be investigated.
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The central fatigue hypothesis postulates that an exercise-induced rise in brain TRP stimulates 5HT synthesis and release [producing fatigue; e.g., see Davis (2,34)]. But, this portion of the hypothesis is too broad, given that: 1) the ability of a rise in brain TRP to stimulate 5HT synthesis and release depends on the firing rate of 5HT neurons and 2) one cannot assume that the firing rate of all 5HT neurons will respond (or will not respond) in the same way to exercise. Regarding the firing rate and TRP-related changes in 5HT synthesis, for example, if 5HT neurons are turned off in rats by the administration of 8-hydroxy-2-(di-n-propylamino)-tetralin [8-OH-DPAT], an agonist at inhibitory 5HT autoreceptors on 5HT neurons (35), 5HT synthesis declines, and the increase in 5HT synthesis that follows a rise in brain TRP is markedly attenuated (see Fig. 1) (36). Regarding the firing rate and TRP-related changes in 5HT release, in vivo microdialysis studies in hippocampus show that when 5HT release in hippocampus is low, it does not respond to TRP injection. Moreover, 5HT release does increase notably after TRP injection when 5HT neurons, projecting into the hippocampus, are activated by electrical stimulation. And, the ability of electrical stimulation to enhance a TRP-induced rise in 5HT release is dose related, in that the greater the frequency of stimulation, the larger the effect of TRP on 5HT release (37).
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Direct electrical recording of 5HT neurons projecting into the dorsal horn of the spinal cord (from the raphe obscurus nucleus) in cats reveals that these neurons increase their firing rate in response to treadmill exercise (39). In contrast, the electrical activity of rostrally projecting 5HT neurons (from the dorsal raphe nucleus) does not increase with exercise (40). In cats, therefore, such data suggest that an exercise-induced rise in brain TRP should stimulate 5HT synthesis in descending, but probably not ascending 5HT neurons, because neuronal activity directly affects the ability of a rise in TRP to stimulate 5HT synthesis (see above). Such descending 5HT neurons appear to facilitate motor neuron depolarization (41). However, Gerin et al. (42) used microdialysis (a method to capture neurotransmitter released from nerve terminals in a small area) and observed no increase in spinal cord 5HT release in rats running on a treadmill. If correct, this finding suggests that the descending 5HT inputs to spinal cord neurons do not increase their firing rate in response to exercise, and thus, a rise in TRP should not increase 5HT synthesis from descending 5HT terminals. And, Meeusen et al. (43) and Smriga et al. (44) observed increases in 5HT release in microdialysate samples from the hippocampus and hypothalamus, respectively, in treadmill-exercising rats, which indicates an increase in the activity of rostrally projecting 5HT neurons. Further, Meeusen et al. showed that the increase in the hippocampal 5HT release during exercise could be enhanced by an injection of TRP (43), whereas Smriga et al. reported that the increase in hypothalamic 5HT release during exercise could be suppressed by administering BCAA, which should reduce brain TRP concentrations (44). Hence, the rostrally projecting 5HT neurons in rats showed both an increase in firing rate with exercise and sensitivity to a change in TRP level. The findings in rats are less clear, however, when a direct biochemical index of 5HT synthesis is examined. Hence, when Chaouloff measured the actual rate of 5HT synthesis in treadmill-exercising rats instead of just the levels of 5HT and 5-hydroxyindoleacetic acid (which are unreliable predictors of 5HT synthesis), and although exercise increased TRP levels in the hippocampus, midbrain, and corpus striatum, the 5HT synthesis rate increased in the brainstem, declined in the hippocampus, and was unchanged in the striatum (45). Because 5HT synthesis rate and the electrical activity of 5HT neurons are directly coupled (46), the Chaouloff findings suggest that exercise did not stimulate the firing of the rostrally projecting 5HT neurons that were studied. At present, therefore, although the microdialysis findings in the rat brain are consistent and interesting, other available biochemical data in rats are inconsistent with the microdialysis findings. Additionally, the electrophysiology findings in cats are opposite to those in rats, making clear conclusions impossible. It would therefore seem that further studies are needed to resolve the conflicting results, to draw a convincing conclusion regarding which 5HT neurons are active during exercise, and are thus likely to be TRP responsive.
Thoughts on serotonin neurons and central fatigue
To date, physical performance and cognitive function have been the principal outcome measures used in exercise and central fatigue studies (47). Even when pharmacologic tools have been applied to examine the links between 5HT, exercise, and central fatigue, these broad-outcome measures have been employed (48). Such general measures, coupled with a view of CNS 5HT neurons as a single neuronal pool that can be manipulated uniformly by pharmacologic or metabolic means, limit one's ability to conceptualize how to dissect the issue further. This problem is exacerbated by the fact that the phenomenon of interest, central fatigue, appears not to have been defined with much precision until recently (1,34). The discussion above offers evidence that CNS 5HT neurons are not all the same and do not respond to changes in TRP in a uniform manner. To this perspective we can add the fact that subgroups of 5HT neurons function in different brain circuits that control discrete physiologic functions. Such information suggests that it might now be more productive to move forward from earlier work by considering, for example: 1) how particular subgroups of 5HT neurons, and the physiologic functions to which they are linked, change during exercise, 2) whether exercise-induced increases in brain TRP stimulate 5HT synthesis and release within 5HT neuronal subgroups and thereby influence their physiologic functions, and if so, 3) whether such effects sustain or diminish physical performance. For example, caudal brainstem 5HT neurons function as chemosensors in animals, and are stimulated by a rise in blood pCO2 (partial pressure of carbon dioxide). These 5HT neurons project to spinal cord, and stimulate, for example, phrenic nerve motor neurons (to the diaphragm) (49). Consistent with these observations, pharmacologic data suggest that the ventilatory response to exercise is inhibited in animals pretreated with a 5HT antagonist, indicating that the 5HT neurons involved are or become active during exercise (50). Hence, it would be of interest to know if the respiratory response to exercise and pCO2 control during exercise are influenced by treatments that raise or lower 5HT synthesis and release, such as TRP itself and the BCAA (to lower 5HT). If medullary 5HT neurons stimulate respiration when pCO2 begins to rise during exercise, then the rise in 5HT synthesis and release with exercise, if it occurs in the brainstem, would promote this effect, and TRP administration would presumably enhance it, whereas BCAA would antagonize it. However, other data indicate that brainstem 5HT neurons inhibit respiration; moreover, recent data in humans suggest that depletion of CNS 5HT by administering LNAAs (including BCAA) does not modify the respiratory reflex to blood CO2 (51). Hence, the exact functional links among exercise, brainstem 5HT neurons, and breathing are not yet firmly established, and additional studies will be required before these relations are known with certainty.
A second example is the secretion of the hormone renin. Renin secretion is influenced by CNS 5HT neurons, probably a rostral projection from the dorsal raphe nucleus (DRN) to the paraventricular nucleus (PVN), effecting renin secretion by sympathetic outflow (52,53). Renin secretion is increased by exercise [see, for e.g., Volek et al. (54)]. Increasing 5HT function stimulates renin secretion (52,55). Of interest in the present context is that TRP administration stimulates renin secretion, and this effect is blocked by a 5HT antagonist (metergoline) and by renal dennervation, but not by a peripheral decarboxylase inhibitor (55). Hence, if DRN 5HT neurons are activated by or during exercise, TRP administration might enhance exercise-induced renin secretion, whereas BCAA (any LNAA) may antagonize the effect. This issue is of physiologic interest during exercise, given the roles of renin in blood-pressure–control pathways, and in fluid and electrolyte balance. Conceivably, through such a pathway, 5HT neurons can participate in maintaining fluid and electrolyte balance during exercise.
A final example is the contribution of central fatigue to the reduction in voluntary muscle function that occurs with exercise (1). Gandevia defines central fatigue as "a progressive reduction in voluntary activation of muscle during exercise" (1). Contributions to central fatigue presumably arise from many sites within the central nervous system, including populations of 5HT neurons (5,34). Central fatigue appears to be demonstrable using a relatively uncomplicated exercise paradigm in humans: the force of a volitional isometric contraction of a given muscle can be shown to diminish with multiple repetitions, while the force of contraction in response to a tetanic stimulus applied to the muscle, when tested at rest intervals between voluntary contractions, does not change (1,56). This loss of volitional contraction force over time can thus be viewed as an experimentally defined measure of central fatigue. If so, it may result, in part, from changes in spinal reflexes involving sensory inputs from muscle that ultimately slow the firing rates of motor neurons; it may also result from changes in signals to lower motor neurons from upper motor neurons, or from other, indirect inputs that modify communication between upper and lower motor neurons (57,58). The paradigm described by Gandevia seems to offer a straightforward test for 5HT neuronal involvement in central fatigue, because if 5HT neurons are involved, the rate of decline in maximal voluntary force generated during repetitive exercise tests should be greater when TRP is administered, and less when BCAA or other LNAAs are administered [because the rise in 5HT during exercise is posited to promote central fatigue (5)]. The contraction to direct muscle stimulation, however, should remain undiminished when tested between voluntary contractions. Although this paradigm cannot localize an effect of TRP or BCAA to a particular CNS location (e.g., 5HT terminals in cerebral vs. spinal cord vs. other CNS sites), a positive finding would stimulate more detailed investigations for such locations. For example, Jacobs has suggested that the firing rate of descending bulbo-spinal 5HT fibers that facilitate motor neuron excitation slows during exercise, and ultimately contributes to central fatigue (59). If this is the case, such slowed 5HT neurons are not likely to show TRP-induced increases in 5HT synthesis and release (see above), and thus would not be a cause of, but rather a response to, central fatigue. In this case, 5HT neurons projecting rostrally (e.g., perhaps from the dorsal raphe nucleus) that are active during exercise might be the source of a diminished stimulatory down-flow to lower motor neurons in the spinal cord, whether mediated by slowed firing of descending 5HT fibers from the brainstem or pyramidal fibers from the motor cortex. If such were correct, then, for example, transcranial stimulation of cortical motor neurons, monitored for its effect on muscle activity (1,56), might be predictably affected by TRP and BCAA treatment. Again, a positive output would not pinpoint the responsible 5HT subpopulations, but would nonetheless add a level of refinement to the search that does not presently exist.
Conclusions
Exercise increases brain TRP concentrations, but the evidence that the rise is driven by an increase in free TRP pools in blood is very weak. Further exploration for the cause of the rise in brain TRP during exercise is warranted.
Exercise increases 5HT synthesis in and release by some 5HT neurons; a contribution to this effect by the rise in brain TRP during exercise is likely to occur only in those 5HT neurons that are active or become more active during exercise. Those 5HT neurons that are responsive to the exercise-related rise in brain TRP will only become known when further studies identify the 5HT neuronal populations activated by exercise.
Although exercise-induced increases in neuronal 5HT synthesis and release may contribute to the development of central fatigue, current approaches seem insufficient to permit a careful elucidation of such contributions. 5HT neurons participate in brain circuits that control a variety of brain functions, any of which can influence physical performance. Only through the identification of those 5HT neurons that are active during exercise (and thus TRP responsive), and of the roles the brain circuits in which they are embedded play in the control of body functions, will it be possible to evaluate if and how such 5HT neurons contribute to central fatigue.
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FOOTNOTES |
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2 Author Disclosure: J. D. Fernstrom received reimbursement from conference sponsor for travel to International Society for Sports Nutrition annual meeting; scientific advisor to the Amino Vital Sports Science Foundation; consulting agreement with Ajinomoto, Washington, DC.
3 Published findings from the authors' laboratories were supported by the National Institutes of Health.
5 Abbreviations used: BBB, blood–brain barrier; CNS, central nervous system; TRP, tryptophan; 5HT, serotonin, NEFA, nonesterified fatty acids; LNAA, large neutral amino acid.
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