Effects Of Neurotransmission And Environmental Temperature On Exercise Performance And Thermoregulation

Roelands B, Meeusen R Department of Human Physiology and Sports Medicine, Vrije Universiteit Brussel, Belgium

The limits of performance during prolonged exercise have been the subject of numerous physiological and psychological studies. Fatigue has traditionally been attributed to the occurrence of a 'metabolic end point', where muscle glycogen concentrations are depleted, plasma glucose concentrations are reduced, and plasma free fatty acid levels are elevated. However, the causes of fatigue are believed to be of both peripheral and central origin, therefore, fatigue should be acknowledged as a complex phenomenon influenced by both peripheral and central factors.

Central fatigue is a form of fatigue that is associated with specific alterations of CNS functioning that may influence mood, the sensation of effort and tolerance to pain and discomfort.

The ‘Central Fatigue Hypothesis' is based on the assumption that during prolonged exercise the synthesis and metabolism of central monoamines, in particular dopamine (DA), noradrenaline (NA) and serotonine (5-HT) is influenced. An excellent paper by Meeusen et al (2006) gives an overview of research until 2006.

It was first suggested by Newsholme and colleagues (1987) that during prolonged exercise increased brain serotonergic activity may affect the physical and mental efficiency of athletes. Much of the attraction of the hypothesis described by Newsholme and co-workers (1987) was the potential for nutritional manipulation of neurotransmitter precursors to delay the onset of central fatigue, potentially enhancing performance.

In recent years a number of studies have employed pharmacological manipulations to alter the central extracellular neurotransmitter concentrations. The most important neurotransmitters involved are 5-HT, DA and NA. These studies are useful for the true understanding of the effects of an increased neurotransmission on performance (Meeusen et al, 2006).

The capacity to perform prolonged exercise is reduced in a warm environment (Galloway & Maughan, 1997; Parkin et al, 1999). Galloway and Maughan (1997) reported that the exercise capacity of non-heat acclimated males was greatest at 11°C, with a progressive fall in time to fatigue as ambient temperature was increased. However, despite an understanding of the influence of ambient conditions on prolonged exercise capacity, the underlying mechanisms behind the deleterious effects of heat stress are not clear at present.

Fatigue during prolonged exercise in a warm environment may coincide with the attainment of a critical core temperature (Gonzalez-Alonso et al, 1999; Walters et al, 2000), suggesting that there may be a thermal limit to exercise performance. Recent work suggests that hyperthermia may have a direct affect on the CNS (Nielsen et al, 2001; Nybo & Nielsen, 2001).

Nielsen and co-workers (2001) demonstrated that prolonged exercise in the heat was characterised by a progressive reduction in electroencephalogram (EEG) activity from the prefrontal cortex (Nielsen et al, 2001), with an increase in the ratio of α to β frequency bands. This shift towards lower-frequency α-bands is associated with feelings of tiredness and fatigue and is observed during the transition from waking to sleep.

To date there has been little investigation of the influence of pharmacological agents acting on the CNS on the response to prolonged exercise in a warm environment. To explore the possible interaction between high ambient temperature, and possible underlying neurotransmitter drive, we examined the effect of a dual DA/NA reuptake inhibitor on performance, thermoregulation and the hormonal responses to exercise (Watson et al, 2005). Subjects performed 4 trials, ingesting either a placebo or bupropion, prior to exercise in temperate (18oC) or warm (30oC) conditions.

Trials consisted of 60 min cycle exercise at 55% Wmax immediately followed by a time trial. TT performance in the heat was significantly improved by bupropion, but no difference between treatments was apparent in temperate conditions. While TT power output was consistently lower in the heat when compared to temperate conditions, this decrement was attenuated by bupropion.

Two important findings arise from this study: 1) subjects completed a pre-loaded TT 9% faster when bupropion was taken before exercise in a warm environment compared to a placebo treatment. This ergogenic effect was not apparent at 18oC. 2) Seven (of 9) subjects in the heat attained core temperatures equal to, or greater than, 40°C in the bupropion trial, compared to only two during the placebo trial. It is possible to suggest that this drug may enable an individual to dampen or override inhibitory signals arising from the CNS to cease exercise due to hyperthermia, and continue to maintain a high power output.

This response appeared to occur without any change in the subjects’ perceived exertion or thermal sensation, and may potentially increase the risk of developing heat illness. In order to look into the effects of chronic changes in central neurotransmission, high ambient temperature and prolonged exercise performance, bupropion was administered for 10 days (Roelands et al, in submission). The experiment was performed with the same protocol used in the acute bupropion study (Watson et al, 2005), the only difference was that there were only trials in 30°C.

In contrast to acute BUP administration, chronic BUP did not influence performance of a preloaded time trial in 30°C and subjects did not reach core temperature values as high as the ones observed during the acute BUP study. The exact mechanism for these observed discrepancies between chronic and acute BUP administration is not yet clear, but it seems possible that chronic administration results in an adaptation of central neurotransmitter homeostasis, resulting in a different response to the drug.

Bupropion is a dual reuptake inhibitor for both DA and NA. Since the increase in central catecholaminergic neurotransmission may, in part, attenuate the loss of performance when exercise is performed in warm environmental temperatures (Watson et al, 2005) and dopamine (DA) is involved in both motor behaviour and motivation (Meeusen et al, 2006), it was interesting to elucidate the specific role of DA and NA in this process. Two studies were performed to research this.

The same protocol as in the acute bupropion study (Watson et al, 2005) was used. Acute DA reuptake inhibition (methylphenidate) resulted in a significant improvement in the time to complete a predetermined amount of work in a warm environment. This ergogenic effect was not apparent at 18°C. Core temperature in the warm methylphenidate trial increased to a mean of 40.0 ± 0.6°C with 4 out of 8 subjects reaching core temperatures above 40°C and 1 subject attaining 41°C after exercise.

However, no differences between placebo and methylphenidate were apparent in the subjects’ RPE and perceived thermal stress. These results not only suggest that methylphenidate exerts equal or greater effects on exercise performance, metabolic heat production and hormonal responses than previously demonstrated with bupropion, they also raise questions over the possible harmful effects of this drug can affect when combined with hard exercise undertaken in warm environmental conditions. Given that many thousands of patients, many of whom are children diagnosed with attention deficit hyperactivity syndrome, take methylphenidate on a daily basis, this finding raises some obvious concerns.

These data appear to suggest that a combination of dopamine reuptake inhibition and exercise under conditions of heat stress may limit an individuals perception of effort and thermal stress and consequently increase the risk of developing potentially serious heat illness (Roelands et al, 2008a). NA reuptake inhibition (reboxetine) on the other hand resulted in a significant decrease in the time to complete a predetermined amount of work in both normal and warm environmental temperature.

Inhibition of the reuptake of NA did not induce hyperthermia in healthy subjects. Manipulation of the NA neurotransmitter system rather induced feelings of cold and a non-significant decrease in core temperature, although there were no changes in the perception of effort (Roelands et al, 2008b). These studies show that, in contrast to prolonged exercise combined with manipulation of central neurotransmission in normal ambient temperature (18°C), addition of heat stress to this combination influences the effects on performance and core temperature. Obviously the DA and NA neurotransmitter system have different effects in humans.

The reuptake inhibition of DA has an ergogenic effect and increases core temperature above 40°C, while the reuptake inhibition of NA has negative effects on performance and does not change core temperature compared to the placebo trial. The effects of the acute administration of the dual DA/NA reuptake inhibitor (bupropion) in the heat seem to be mediated predominantly by the DA neurotransmitter system. These results further confirm that fatigue during prolonged exercise in the heat is influenced by central mechanisms.


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