HT agonists exercise duration

5-HT in exercise

5-HT receptor up-regulation in CFS

5-HT receptor down-regulation in trained athletes

Fig. 3.5 Summary of the possible involvement of brain 5-hydroxytryptamine (5-HT) and the hypothalamic-pituitary axis (HPA) in the genesis of fatigue induced by exercise and associated with chronic fatigue syndrome (CFS). L-tryptophan (the precursor for 5-HT synthesis) and branched chain amino acids (BCAA) compete for the same transporter into the brain so that when muscles are exercising and using BCAA more L-tryptophan is able to enter the brain via the transporter. CRH = corticotrophin-releasing hormone. See text for references.

Exercise-induced fatigue

The amino acid tryptophan is the precursor for 5-HT synthesis and enters the brain via a carrier (transporter) system that can also be used by branch-chain amino acids (BCAA). During exercise, BCAA are transported into the active skeletal muscles and hence the levels free in the plasma decrease, leading to a decreased competition with tryptophan and hence an increase in the entry of tryptophan into the brain. This is argued to lead to an increase in the synthesis of 5-HT in the brain, although whether this is generalized or regionalized has not been determined. As central 5-HT was known to be involved in sleep, aggression, and mood (depression), it was hypothesized that an elevation in central 5-HT could mediate or contribute to the central component(s) of the fatigue occurring during and after heavy exercise (Newsholme and Blomstrand 1995). In human volunteers receiving single 5 mg oral doses of (-) tryptophan, subjects rated themselves as 'more slowed down' than on placebo, and mood self-rating scales revealed a significant increase in subjects' ratings of drowsiness, muzziness, and mental slowness (Greenwood et al. 1975).

Hypothalamic 5-HT receptor function is down-regulated in endurance-trained athletes (Jakeman et al. 1994). The 5-HT hypothesis has been studied directly in healthy volunteers by examining the effect of ingestion of BCAA on the fatigue scores during exercise. The perceived exertion and mental fatigue scores were reduced by ingestion of BCAA in subjects exercising on a bicycle ergometer at 70% of their VO2 max (maximum volume of oxygen consumption) for 60 min (Blomstrand et al. 1997). However, there was no significant effect in subjects exercising maximally, an observation which may be consistent with evidence showing that consumption of BCAA increased performance in slower but not faster marathon runners (Newsholme and Blomstrand 1995). These results suggest that a study of the effects of BCAA may be warranted in patients with cancer-related fatigue once further evidence supporting an involvement is forthcoming (see below).

The possible role of central 5-HT has also been investigated using drugs to modify serotonergic transmission. In healthy volunteers the selective serotonin reuptake inhibitor (SSRI) paroxetine, given as a single 20 mg oral dose, was shown to reduce the time that exercise on a bicycle ergometer at 70% VO2 max could be sustained (Wilson and Maughan 1992). A similar study used the 5-HT1a receptor agonist buspirone in subjects exercising at 80% VO2 max, and showed a reduction in the time subjects could exercise, and an increase in the perceived exhaustion score (Marvin et al. 1997).

The results from the above studies are consistent in implicating an elevation in central 5-HT in the genesis of the 'central fatigue' associated with exercise, defined as 'a progressive exercise-induced reduction in voluntary activation of muscle' (Gandevia et al. 1995). The site(s) at which 5-HT is elevated in humans remains to be identified, but sustained exercise in rats demonstrated increased 5-HT levels in the hypothalamus and brainstem but not in four other areas studied (Blomstrand et al. 1989). Other studies in rats have also shown that administration of 5-HT produced a dose-related decrease in running (Bailey et al. 1992), and an improvement in performance by addition of an antagonist (Bailey et al. 1993). In cats, injection of 5-HT into the lateral ventricle of the brain produced 'lethargy' and 'diminished muscular tone' (Gaddum and Vogt 1956).

Chronic fatigue syndrome

5-HT has also been the focus of attention in patients with CFS, but this has been because a number of pituitary hormones have their secretion influenced by 5-HT. In patients with CFS (but not primary depression, potentially co-morbid with chronic fatigue, see below) the 5-HT1a agonist buspirone and the 5-HT2 agonist D-fenfluramine evoke an enhanced secretion of prolactin (Cleare et al. 1995; Bakheit et al. 1992; Sharpe et al. 1996, 1997). Overall these results suggest an up-regulation/hypersensitivity of a population of central 5-HT receptors in the hypothalamus and this contrasts with a down-regulation reported in endurance trained athletes (Jakeman et al. 1994).

These types of study could readily be undertaken in patients with cancer-related fatigue.

How could cancer and its therapy modify serotonin metabolism?

The above sections have identified ways in which changes in 5-HT and/or its receptors may alter in fatigue, but how could such changes be brought about by cancer and its therapy? The proinflammatory cytokines are well known to induce fatigue when administered (Blesch et al.1991; Borish et al. 1998; Holmes et al. 1988; Moldawer and Figlin 1988; Piper et al. 1989; Winningham et al.1994) and tumour necrosis factor (TNF) has been shown to prevent proteosome-dependent degradation of the regulator of G-protein signalling, RGS7 (Benzing et al. 1999). This has been proposed to produce changes in central nervous system (CNS) neurotransmission leading to behavioural changes associated with an inflammatory response (for example lethargy, fever, anorexia). Several pieces of evidence implicate the proinflammatory cytokines in the possible modulation of serotonergic transmission which itself plays a key role in the neuropharmacology of sleep:

1. The proinflammatory cytokine TNF is elevated in the circulation of patients with cancer and is further elevated by radiotherapy (Bianco et al. 1991; Hallahan et al. 1993), as is IL-1 (Greenberg et al. 1993). Central nervous system neurons increase synthesis of TNF-a in response to radiation (Hong et al. 1995).

2. TNF and IL-6 levels have been reported to be elevated in several studies of patients with CFS (Borish et al. 1998; Chao et al. 1990; Patarca et al. 1994).

3. TNF has been shown to increase neuronal release of 5-HT and to double the levels of the 5-HT transporter (Mossner et al. 1998), which is the main mechanism responsible for removal of 5-HT from the synaptic space. The net effects of these actions upon synaptic transmission, if they occurred in the same location, are impossible to predict.

4. TNF can increase the circulating level of L-tryptophan the precursor for 5-HT synthesis (Pauli et al. 1998).

It must be emphasized that the above observations are from a combination of clinical and preclinical studies and from them it is not possible to predict exactly what will happen to either synaptic 5-HT levels or 5-HT receptors. However, taken together with the studies of exercise and CFS they do provide a possible mechanistic link between cytokines, 5-HT, and fatigue that merits further investigation. If cytokines are involved then one major issue is how systemic cytokines could influence the CNS as they do not readily penetrate the brain. There are at least two possibilities, both of which could be involved in the genesis of fatigue:

(1) activation of peripheral afferents (for example the vagus) which project to the brain (see above);

(2) access to the brain via the circumventricular organs (for example the area postrema or anterior hypothalamus) where the blood-brain barrier is relatively permeable.

There is evidence that macrophage-like (phagocytic) cells in the circumventricular organs and the choroid plexus (e.g. in the region of the hypothalamus) produce IL-1 which can then diffuse into the brain to activate neurons and release other neuroactive agents (e.g. prostaglandin E2) (Konsman et al. 2002).

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