Maria Francesca Piacentini

Central Fatigue The Serotonin Hypothesis and Beyond

The original central fatigue hypothesis suggested that an exercise-induced increase in extracellular serotonin concentrations in several brain regions contributed to the development of fatigue during prolonged exercise. Serotonin has been linked to fatigue because of its well known effects on sleep, lethargy and drowsiness and loss of motivation. Several nutritional and pharmacological studies have attempted to manipulate central serotonergic activity during exercise, but this work has yet to provide robust evidence for a significant role of serotonin in the fatigue process. However, it is important to note that brain function is not determined by a single neurotransmitter system and the interaction between brain serotonin and dopamine during prolonged exercise has also been explored as having a regulative role in the development of fatigue. This revised central fatigue hypothesis suggests that an increase in central ratio of serotonin to dopamine is associated with feelings of tiredness and lethargy, accelerating the onset of fatigue, whereas a low ratio favours improved performance through the maintenance of motivation and arousal. Convincing evidence for a role of dopamine in the development of fatigue comes from work investigating the physiological responses to amphetamine use, but other strategies to manipulate central catecholamines have yet to influence exercise capacity during exercise in temperate conditions. Recent findings have, however, provided support for a significant role of dopamine and noradrenaline (norepinephrine) in performance during exercise in the heat. As serotonergic and catecholaminergic projections innervate areas of the hypothalamus, the thermoregulatory centre, a change in the activity of these neurons may be expected to contribute to the control of body temperature whilst at rest and during exercise. Fatigue during prolonged exercise clearly is influenced by a complex interaction between peripheral and central factors.

Acute dopamine/noradrenaline reuptake inhibition enhances human exercise performance in warm, but not temperate conditions

Nine healthy endurance‐trained males were recruited to examine the effect of a dual dopamine/noradrenaline reuptake inhibitor on performance, thermoregulation and the hormonal responses to exercise. Subjects performed four trials, ingesting either a placebo (pla) or 2 × 300 mg bupropion (bup), prior to exercise in temperate (18°C) or warm (30°C) conditions. Trials consisted of 60 min cycle exercise at 55%Wmax immediately followed by a time trial (TT). TT performance in the heat was significantly improved by bupropion (pla: 39.8 ± 3.9 min, bup: 36.4 ± 5.7 min; P= 0.046), but no difference between treatments was apparent in temperate conditions (pla: 30.6 ± 2.2 min, bup: 30.6 ± 1.9 min; P= 0.954). While TT power output was consistently lower in the heat when compared to temperate conditions, this decrement was attenuated by bupropion. At the end of the TT in the heat, both core temperature (pla 39.7 ± 0.3°C, bup 40.0 ± 0.3°C; P= 0.017) and HR (pla 178 ± 7 beats min−1, bup 183 ± 12 beats min−1; P= 0.039), were higher in the bupropion trial than in the placebo. Circulating pituitary and adrenal hormone concentrations increased throughout exercise in all trials. Circulating serum prolactin was elevated above temperate levels during exercise in a warm environment (P < 0.001). These data indicate that performance in warm conditions is enhanced by acute administration of a dual dopamine/noradrenaline reuptake inhibitor. No such effect was apparent under temperate conditions. It appears that bupropion enabled subjects to maintain a greater TT power output in the heat with the same perception of effort and thermal stress reported during the placebo trial, despite the attainment of a higher core temperature.

The effects of acute dopamine reuptake inhibition on performance.

INTRODUCTION Acute bupropion (dopamine/noradrenaline reuptake inhibitor) administration significantly improved time trial performance and increased core temperature in the heat (30 degrees C). PURPOSE The present study was performed to examine the effect of a dopaminergic reuptake inhibitor on exercise capacity and thermoregulation during prolonged exercise in temperate and warm conditions. METHODS Eight healthy well-trained male cyclists participated in this study. Subjects ingested either placebo (PLA; 20 mg) or methylphenidate (MPH; Ritalin; 20 mg) 1 h before the start of exercise in temperate (18 degrees C) or warm (30 degrees C) conditions and cycled for 60 min at 55% Wmax, immediately followed by a time trial (TT; PLA18 and MPH18; PLA30 and MPH30) to measure exercise performance. RESULTS MPH did not influence TT performance at 18 degrees C (P = 0.397). TT was completed 16% faster in MPH30 (38.1 +/- 6.4 min) than in PLA30 (45.4 +/- 7.3 min; P = 0.049). In the heat Tcore was significantly higher at rest (P = 0.009), and throughout the TT in MPH30 (P < 0.018), reaching values above 40 degrees C. Throughout MPH30, heart rates were significantly higher (P < 0.05). CONCLUSIONS These results show that MPH has a clear ergogenic effect that was not apparent in 18 degrees C. The combination of a dopamine reuptake inhibitor and exercise in the heat clearly improved performance and caused hyperthermia without any change in the perception of effort or thermal stress compared with the PLA trial. This response may potentially increase the risk of developing heat illness during exercise in individuals taking drugs of this nature.

Influence of brain catecholamines on the development of fatigue in exercising rats in the heat

The purpose of the present study was to identify the effects of an acute injection of a dual dopamine (DA)/noradrenaline (NA) reuptake inhibitor (bupropion) on exercise performance, thermoregulation and neurotransmitters in the preoptic area and anterior hypothalamus (PO/AH) of the rat during exercise in the heat. Body core temperature (Tcore), brain temperature (Tbrain) and tail skin temperature (Ttail) were measured. A microdialysis probe was inserted in the PO/AH, and samples for measurement of extracellular DA, NA and serotonin (5‐HT) levels were collected. Rats received either bupropion (17 mg kg−1; hot‐BUP) or saline (1 ml kg−1; hot) 20 min before the start of exercise and ran at a speed of 26 m min−1 until exhaustion in a warm environment (30°C). Rats also ran until exhaustion in a cool environment (18°C; cool). Running time to exhaustion was significantly influenced by the ambient temperature, and it was increased by bupropion in the heat (cool, 143.6 ± 21 min; hot, 65.8 ± 13 min; hot‐BUP, 86.3 ± 7.2 min). Tcore and Tbrain at exhaustion were significantly higher in the bupropion group compared to the cool and hot groups, respectively. Ttail measured at exhaustion was not significantly different between the two hot conditions. Extracellular concentrations of DA and NA in the PO/AH increased during exercise, and was significantly higher in the bupropion than in cool and hot groups (P < 0.05). No differences were observed between groups for 5‐HT levels. These results suggest that DA and NA in the PO/AH might be responsible for the increase in exercise performance and Tcore and Tbrain in the bupropion group in hyperthermia. Moreover, these results support previous findings in humans that acute bupropion ingestion increases Tcore during exercise in the heat, indicating the possibility of an important role for DA and NA in thermoregulation.

Acute norepinephrine reuptake inhibition decreases performance in normal and high ambient temperature

Combined inhibition of dopamine (DA)/norepinephrine (NE) reuptake improves exercise performance and increases core temperature in the heat. A recent study demonstrated that this effect may primarily be related to increased DA activity. NE reuptake inhibition (NERI), however, has received little attention in humans, certainly in the heat, where central fatigue appears to be a main factor influencing performance. Therefore the present study examines the effect of NERI (reboxetine) on exercise capacity, thermoregulation, and hormonal response in normal and high temperature. Nine healthy well-trained male cyclists participated in this study. Subjects ingested either placebo (Pla; 2 x 8 mg) or reboxetine (Rebox; 2 x 8 mg). Subjects exercised in temperate (18 degrees C) or warm (30 degrees C) conditions and cycled for 60 min at 55% W(max) immediately followed by a time trial (TT; Pla18/Rebox18; Pla30/Rebox30) to measure exercise performance. Acute NERI decreased power output and consequently exercise performance in temperate (P = 0.018) and warm (P = 0.007) conditions. Resting heart rate was significantly elevated by NERI (18 degrees C: P = 0.02; 30 degrees C: P = 0.018). In Rebox18, heart rate was significantly higher than in the Pla18, while in the heat no effect of the drug treatment was reported during exercise. In Rebox30, all hormone concentrations increased during exercise, except for growth hormone (GH), which was significantly lower during exercise. In Rebox18, prolactin (PRL) concentrations were significantly elevated; GH was significantly higher at rest, but significantly lower during exercise. In conclusion, manipulation of the NE system decreases performance and modifies hormone concentrations, thereby indicating a central NE effect of the drug. These findings confirm results from previous studies that predominantly increased DA activity is important in improving performance.

No effect of a noradrenergic reuptake inhibitor on performance in trained cyclists

INTRODUCTION According to the central fatigue hypothesis, serotonin (5-HT) is related to fatigue, whereas the noradrenergic system is primarily concerned with arousal and motivation, and therefore hypothesized to enhance performance. The purpose of the present study was to examine the effects of a selective noradrenergic reuptake inhibitor (reboxetine 2 x 4 mg REB-NARI) on exercise performance. METHODS Seven healthy well-trained male cyclists (age: 23 +/- 1.7 yr, height: 182 +/- 5.8 cm, weight: 73.5 +/- 8.5 kg, VO2max: 73.5 +/- 6.4 mL x kg(-1) x min(-1), Watt(max): 376 +/- 11.7 W) participated to the study. Subjects completed two endurance tests (time trials) starting at 65% Wmax in a double-blind randomized cross-over design. Blood samples were collected for adrenocorticotropin, prolactin, cortisol, growth hormone (GH), beta-endorphins, and catecholamines and were taken at 30-min time intervals until the end of exercise. Performance was analyzed with a paired t-test, whereas data for hormonal and metabolic differences during the trials were analyzed using an ANOVA repeated measures design and an LSD-planned comparisons test. Significance level was set at P < 0.05. RESULTS Performance was not influenced by the NARI (REB: 97 min +/- 3 min, placebo (PLAC): 92 min +/- 1 min). All hormones increased during exercise except for GH in the REB trial, which was significantly lower than PLAC. The other hormones were significantly higher in the REB trial versus the PLAC trial at the end of exercise and during recovery. CONCLUSION In conclusion, the results demonstrate that the drug had a central effect. In particular, the higher resting GH concentrations indicated a marked and selective noradrenergic effect of REB. However, performance was not influenced by a selective NARI in well-trained endurance athletes.

Diagnosing overtraining in athletes using the two-bout exercise protocol

Objective In this work, whether a two-bout exercise protocol can be used to make an objective, immediately available distinction between non-functional over reaching (NFO) and overtraining syndrome (OTS) was studied. Design Underperforming athletes who were diagnosed with the suspicion of NFO or OTS were included in the study. Recovery of the athletes was monitored by a sports physician to retrospectively distinguish NFO from OTS. Setting Sports medicine laboratory Participants The protocol was started and completed by 10 underperforming athletes. NFO was retrospectively diagnosed in five athletes, and OTS was diagnosed in five athletes. Interventions A two-bout maximal exercise protocol was used to measure physical performance and stressinduced hormonal reactions. Main outcome measurements Exercise duration, heart rate and blood lactate concentration were measured at the end of both exercise tests. Venous concentrations cortisol, adrenocorticotrophic hormone (ACTH), prolactin and growth hormone were measured both before and after both exercise tests. Results Maximal blood lactate concentration was lower in OTS compared with NFO, while resting concentrations of cortisol, ACTH and prolactin concentrations were higher. However, sensitivity of these measures was low. The ACTH and prolactin reactions to the second exercise bout were much higher in NFO athletes compared with OTS and showed the highest sensitivity for making the distinction. Conclusions NFO might be distinguished from OTS based on ACTH and prolactin reactions to a two-bout exercise protocol. This protocol could be a useful tool for diagnosing NFO and OTS; however, more data should be collected before this test can be used as the gold standard.

Hormonal responses during prolonged exercise are influenced by a selective DA/NA reuptake inhibitor

Objective: A decrease in dopamine activity is thought to lead to a reduction in motivation and arousal and therefore to the “central” component of fatigue. The purpose of the present study was to investigate the effects of a dopamine (DA) noradrenaline (NA) reuptake inhibitor, bupropion (Zyban™), on exercise performance and on the hormonal response to exercise. Methods: Eight healthy well trained male cyclists (Wattmax 397±15 W) participated in the study. Subjects completed one maximal exercise test (to determine maximal power output Wattmax), and two endurance performance tests (time trials) in a double blind randomised cross-over design. Subjects took either placebo capsules (lactose) or 2×300 mg bupropion (BUP). Blood samples were collected for adrenocorticotropin (ACTH), prolactin, cortisol, growth hormone, beta-endorphins, and catecholamines. Results: Performance was not influenced by BUP (placebo: 89±1 min; BUP 2×300 mg: 89±0.7 min). All hormones increased during exercise in all trials. Cortisol plasma concentrations were significantly higher in the BUP trial at rest, at min 60, and at the end of exercise, while beta-endorphins were higher in the BUP trial at the end of exercise and during recovery, and ACTH at the end of exercise. Conclusion: From the present results, we can conclude that bupropion had a more marked central noradrenergic effect (compared to dopaminergic) on the hormonal response to exercise, but no effect on the outcome of performance.

Exercise as a countermeasure to psycho-physiological deconditioning during long-term confinement

Confinement studies are performed to simulate the psychological effects that may be experienced on a long-term space flight. A general psycho-physiological model assumes that mood and cognitive functioning are impaired during confinement as a result of an absence of physical activity. The aim of the MARS500 study initiated by the Institute of Biomedical Problems (IBMP) and the European Space Agency (ESA) is to gather data, knowledge and experience to help prepare for a real mission to Mars. A test run with 105 days of isolation was performed prior to 520 days of isolation. Psycho-physiological data of this study are presented here. We hypothesized that exercise, as it has been shown in laboratory settings, would be able to prevent and counteract mood changes during isolation. Electrocortical data (EEG) and a self report on current psychological and physical state were recorded several times prior to and after exercise during the isolation period. Data revealed a clear effect of exercise on mood and electrocortical activity. Moreover, it was shown that mood and brain cortical activity decreased during the first 11 weeks of isolation and reached baseline again in the last week of isolation. A correlation analysis revealed a significant relation between mood data and electrocortical activity. We conclude (1) that confinement is accompanied by psycho-physiological changes and (2) that exercise is a suitable method to counteract psycho-physiological deconditioning during confinement.

Type 1 diabetes-associated cognitive decline: A meta-analysis and update of the current literature

Type 1 diabetes (T1D) can have a significant impact on brain structure and function, which is referred to as T1D‐associated cognitive decline (T1DACD). Diabetes duration, early onset disease, and diabetes‐associated complications are all proposed as factors contributing to T1DACD. However, there have been no comparisons in T1DACD between children and adults with T1D. To obtain a better insight into the occurrence and effects of T1DACD in T1D, the aim of the present meta‐analysis was to investigate differences between children and adults and to analyse factors contributing T1DACD.