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1 Department of Clinical Biochemistry, Grampian University Hospital NHS Trust, Foresterhill, Aberdeen, AB25 2ZD, UK 2 School of Medical Sciences, University Medical School, Foresterhill, Aberdeen, AB25 2ZD, UK 3 School of Sport & Exercise Sciences, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
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(Received 20 April 2004;
accepted after revision 17 July 2004; first published online 24 August 2004)
Corresponding author A. T. Strachan: Department of Clinical Biochemistry, Grampian University Hospital NHS Trust, Foresterhill, Aberdeen, AB25 2ZD, UK. Email: a.t.strachan{at}arh.grampian.scot.nhs.uk
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One exception, however, was a study that showed an improvement in exercise capacity following BCAA supplementation before exercise of modest intensity in a warm environment (Mittleman et al. 1998). This may be important because it is generally agreed that substrate availability can account for the fatigue that occurs during prolonged exercise in cool or temperate environments (Hargreaves et al. 2004). It is equally clear, however, that glycogen availability does not limit exercise capacity in the heat and there is no clearly defined mechanism by which hyperthermia causes the subjective decision to terminate exercise (Galloway & Maughan, 1997; Hargreaves & Febbraio, 1998).
In contrast to the results of studies which have attempted to manipulate Trp uptake, some pharmacological evidence from both animal and human studies is consistent with the suggestion that an increase in central 5-HT neurotransmission is detrimental to the performance of prolonged exercise (Bailey et al. 1992, 1993; Wilson & Maughan, 1992; Davis et al. 1993; Struder et al. 1998). In humans, three studies have demonstrated that administration of selective serotonin re-uptake inhibitors (SSRI) is effective in reducing the ability to perform prolonged exercise (Wilson & Maughan, 1992; Davis et al. 1993; Struder et al. 1998). In two of these studies, a single 20 mg dose of paroxetine, administered 5 h before exercise commenced, reduced exercise capacity. Selective serotonin re-uptake inhibitors effectively increase synaptic levels of 5-HT by selective blockade of the 5-HT re-uptake transporter, but the underlying mechanisms that influence exercise capacity remain unclear.
One aspect of central 5-HT function that has largely been ignored in the exercise studies referred to above is the role of 5-HT in thermal regulation (Feldberg & Myers, 1964). This may be relevant because elevated body temperature is considered a major factor in the development of fatigue during prolonged exercise (Gonzalez-Alonso et al. 1999). Both the capacity for exercise and body temperature are significantly influenced by ambient temperature (Galloway & Maughan, 1997; Parkin et al. 1999). The detrimental effects of high ambient temperature on exercise capacity are not readily explained in terms of hyperthermia, hypohydration or muscle glycogen depletion (Galloway & Maughan, 1997; Hargreaves & Febbraio, 1998). The failure of changes in peripheral factors to account for the onset of fatigue in the heat suggests that central components, including an increased central 5-HT activity, may be involved. In man, this suggestion is partly supported by the observation that peripheral markers of central 5-HT activity such as prolactin and cortisol (Van de Kar, 1997) are elevated during exercise in a warm but not in a cool environment (Pitsiladis et al. 2002).
The available experimental evidence suggests that there could be an association between central 5-HT activity and thermal regulation that, in turn, may influence exercise capacity. The purpose of the present experiment was to examine whether selective blockade of 5-HT re-uptake transporters by paroxetine has any effect on exercise capacity, thermal regulation and neuroendocrine response during prolonged exercise in a warm environment.
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of 56 (5) ml min –1 kg–1. Subjects were recreationally active individuals; most were cyclists active in local clubs but none was acclimatized to exercise in a warm environment. None of the subjects were taking any prescribed medicines. All subjects were fully informed of the nature and the purpose of the study and gave their written consent to participate prior to commencing the study. The Joint Ethical Committee of Grampian Health Board and the University of Aberdeen had granted approval of this study.
Each subject's power output for the exercise trial was determined following a discontinuous incremental maximum oxygen uptake test performed at room temperature (20–24°C) on an electrically braked cycle ergometer (Gould Corival 300, Sensormedics, Rugby, UK). All subjects performed three cycle rides to exhaustion at 60% of their 
. The first test was conducted at 32°C and 49 (7)% relative humidity and served to familiarize the subjects with the experimental protocol and with the sensation of exercise to fatigue. After 15 min of cycling in the familiarization trial, expired gas was collected to allow evaluation of power output for use in experimental trials. The two experimental trials were performed at an ambient temperature of 32°C with a relative humidity of 60 (8)%. During exercise, subjects cycled at 60%
until volitional fatigue, which was defined as an inability to continue or maintain a pedal cadence greater than 60 r.p.m. The ambient temperature for the experimental trials was maintained using a climatic chamber and the circulating air velocity within the chamber was 1–2 m s–1. The trials began between 17.00 and 18.00 h and were carried out on the same day of the week, 1 or 2 weeks apart.
Paroxetine (Seroxat, Smith-Kline-Beecham) was administered per os in a single dose of 20 mg. Placebo and paroxetine were prepared in similar dextrose-filled gelatine capsule and administered in a double blind fashion. The trials were conducted in a Latin square crossover, randomised design. Confirmation of drug ingestion was made by Toxi-Laboratory screen (Microgen Bioproducts Ltd, Camberly, UK). The subjects were instructed to rest or participate in only light training on the day before the experimental trials. The subjects were instructed to record their dietary intake and physical activity for 2 days before the first experiment trial; their dietary intake and physical activity were then replicated before the remaining experimental trial.
On the day of the trial, the drug or placebo was administered orally 5 h before arrival at the laboratory and was followed by a meal that was replicated before each trial. Subjects were instructed to drink 300–500 ml of water 3 h before arrival at the laboratory to ensure that they were well hydrated before commencing exercise. On arrival at the laboratory, the cycle ergometer was adjusted to suit the needs of the individual. After voiding, the nude body mass of subjects was measured before subjects inserted a rectal thermistor 10 cm beyond the anal sphincter and positioned a heart rate monitor around their chest (Polar Sports Tester PB3000, Bodycare Ltd, Kenilworth, UK). Subjects then rested in a sitting position for 25 min in a comfortable environment (22–24°C).
For the first 10 min of seated rest, the subject's hand was immersed in hot (40–42°C) water to allow arterialized venous blood to be drawn. After 10 min, the hand was dried and a venous cannula was then inserted into a lower forearm vein. The cannula was kept patent by an injection of heparinized saline after each sample was drawn. Resting blood samples (7.5 ml) were obtained 5 and 15 min after placement of the cannula. For these and the subsequent blood samples, 2.5 ml aliquots were immediately dispensed into a plain tube containing no anticoagulant, one with K3-EDTA anticoagulant and one with fluoride oxalate preservative. The blood in the plain tube was allowed to clot and then centrifuged. Serum was separated by centrifugation and stored at –20°C until the determination of prolactin and cortisol concentrations. The blood from the K3-EDTA tube was used for the determination of haemoglobin (Hb) concentration and spun haematocrit (Hct). The fluoride oxalate tube was stored on ice until centrifugation and the plasma collected was stored at –20°C for the determination of glucose and lactate concentration. Baseline recordings of rectal temperature (Tre) and heart rate were made at 5 min intervals following cannula insertion.
Immediately following collection of the second resting blood sample the subjects transferred to the climatic chamber, where they began exercise within 90–120 s of entering the chamber. The subjects were asked to maintain a pedal cadence of between 70 and 90 r.p.m. Blood samples (7.5 ml) were drawn during exercise at 15 min intervals and at the cessation of exercise. Ratings of overall perceived exertion were obtained every 10 min throughout exercise using the Borg category scale (Borg, 1998). Ambient temperature (Ta), Tre and heart rate were recorded every 5 min throughout exercise. No fluid to drink was provided during the exercise test. Time to exhaustion was noted in all trials. Subjects were not informed of the time elapsed during or at the end of each of the trials. At the end of the trials, the heart rate monitor and rectal probe were removed and the subject's nude body mass was again measured. The difference between body mass before and after exercise was calculated to provide an estimate of fluid loss during exercise, with losses due to blood sampling and substrate exchange being ignored.
The serum concentrations of prolactin (IU l–1) and cortisol (nmol l–1) were measured using a heterogeneous sandwich magnetic separation assay on an Immuno-1 System (Bayer Diagnostics, Basingstoke, UK). For the duration of the trials, the intra-assay variation (c.v.) for prolactin and cortisol was 3.1 and 3.8%, respectively. Plasma glucose (mmol l–1) and lactate (mmol l–1) concentrations were determined using hexokinase and lactate dehydrogenase methods, respectively, on a Dimension Clinical Chemistry system (Dade Behring Ltd, Walton, Milton Keynes, UK). Haemoglobin concentration was determined using a cyan-methaemoglobin method (Dacie & Lewis, 1968). Haemoglobin concentration and spun Hct were used for the calculation of percentage changes in plasma volume relative to the initial resting sample obtained before exercise began (Dill & Costill, 1974).
The normality of distribution of the data was assessed using the Kolmogorov–Smirnov test. Normally distributed data are presented in the text and figures as mean (S.D.). Data not normally distributed are presented in the text and figures as median (range). Data were analysed by two-way analysis of variance to compare differences between treatments. Repeated measures one-way analysis of variance using Friedman's test and Dunn's post hoc test was used to compare variation within individual trials. Subsequent statistical tests to compare paired groups were performed using Wilcoxon's signed rank sum test. Significance was accepted at P < 0.05.
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The effects of acute paroxetine or selective 5-HT re-uptake inhibitor (SSRI) administration on core temperature are inconsistent (Clark & Lipton, 1986). In the present study, a small increase in basal Tre was observed following paroxetine administration. This observation is consistent with the suggestion that paroxetine acts as a postsynaptic 5-HT agonist and induces a rise in Tre by an increase in postsynaptic hypothalamic 5-HT activity (Lin et al. 1998). A reduction in core temperature might have been expected if paroxetine administration had resulted in activation of presynaptic autoreceptors in 5-HT cell bodies of the dorsal raphe nuclei and induced a decrease in the cell firing rate (Hillegaart, 1991).
In the present study, the very small but consistent elevation in basal Tre following paroxetine administration was maintained throughout exercise but had no detrimental effect on exercise capacity (Gonzalez-Alonso et al. 1999). This is in contrast to the findings of acclimation (Nielsen et al. 1993) and precooling studies (Bruck & Olschewski, 1987; Lee & Haymes, 1995), which suggest that a modest reduction in Tre before commencement of exercise improves heat storage and delays the attainment of a limiting core temperature, thereby improving exercise capacity and performance (Gonzalez-Alonso et al. 1999). In the present study, none of the subjects attained the critical core temperature (
40°C) that is considered by some to limit exercise performance (Gonzalez-Alonso et al. 1999). The failure of the exercise protocol of the present study to induce sufficient thermal strain to achieve this level of core temperature may limit the findings. Nonetheless, the results do suggest that oral administration of 20 mg paroxetine did not significantly influence the thermoregulatory factors that may limit exercise capacity.
In the present study, the serum concentrations of prolactin and cortisol were measured at rest and during exercise to provide an index of the central 5-HT receptor activity (Van de Kar, 1997). In keeping with previous studies (Sargent et al. 1996; Cowen & Sargent, 1997), the resting concentrations of prolactin and cortisol were not influenced by oral paroxetine administration. Consistent with previous studies, however, the serum concentrations of prolactin increased during the later stages of exercise (Pitsiladis et al. 2002). The prolactin response to exercise in a warm environment has been correlated with the extent of increase in Tre (Melin et al. 1988; Radamski et al. 1998). In the present study, a non-linear relationship was observed between the plasma prolactin concentration and Tre. These prolactin results provide limited support for the suggestion that secretion of hypothalamic mediated hormones into the plasma is initiated by an increase in core temperature above 38–38.5°C (Radamski et al. 1998).
The circulating levels of prolactin are regulated primarily by dopamine occupation of D2 anterior pituitary receptors (Ben-Jonathan, 1985) but can be influenced by postsynaptic 5-HT2a/c receptors located in the paraventricular nucleus of the hypothalamus (Rittenhouse et al. 1993). Exercise-induced increases in prolactin can be abolished by the D2 dopamine agonists bromocriptine and pergolide (De Meirleir et al. 1985; Boisvert et al. 1992), or the 5-HT2a/c receptor antagonist ketanserin (De Meirleir et al. 1985). The failure of paroxetine in the present study to influence the prolactin response suggests that dopamine may be the primary regulator of this hormone, particularly when exercise is performed at a high ambient temperature.
The circulating concentration of cortisol was elevated at the end of exercise in the present study. Previous studies have shown that cortisol responses during exercise are dependent on both intensity and duration of the exercise (Davis & Few, 1973; Luger et al. 1988). The observed cortisol response in the present study is consistent with an increase in hypothalamic–pituitary–adrenal axis activity during exercise (Luger et al. 1987). The failure of paroxetine administration to influence the circulating concentration of prolactin or cortisol raises questions concerning the role of 5-HT in their secretion during exercise. Both pre- and postsynaptic 5-HT receptors are involved in the regulation of cortisol secretion (Van de Kar, 1997) but activation of somatodendritic 5-HT1a autoreceptors on the 5-HT cells in the dorsal raphe nuclei during stressful events may limit cortisol secretion (Matheson et al. 1994). Furthermore, species-dependent terminal 5-HT1b/d autoreceptors regulate the volume of 5-HT released into the synaptic cleft (*). If a concomitant decrease in 5-HT cell firing or a reduction in synaptic 5-HT concentration resulting from 5-HT1a/1b/1d autoreceptor activation following paroxetine administration (Fuller, 1994; Gartside et al. 1992, 1995) did occur in the present study, it was not reflected in attenuated cortisol or prolactin responses.
In the present study, power output was constant throughout exercise but the subjective perception of effort increased over time during exercise. Perceived exertion was not altered by paroxetine administration and this is consistent with the failure of the treatment to affect exercise performance, but is in contrast to a previously reported study in which administration of another SSRI (fluoxetine) increased perceived effort during exercise (Davis et al. 1993). In humans, attempts to alter exercise capacity and perception of effort during physical activity by manipulating the peripheral availability of the 5-HT precursor Trp also remain inconclusive. Blockade of Trp uptake into the brain by BCAA administration before and during prolonged exercise lowers subjective measures of perceived exertion and mental fatigue in some studies (Blomstrand et al. 1991, 1997; Hassmen et al. 1994) but not in others (van Hall et al. 1995; Struder et al. 1998). Conversely, oral administration of Trp before exercise did not increase perceived effort or reduce the ability to perform prolonged exercise (van Hall et al. 1995). Therefore, despite a strong association between central 5-HT activity and mood (Young, 1991), it remains to be seen whether the subjective sensations of effort and fatigue during prolonged exercise are associated with an alteration of 5-HT activity.
In conclusion, acute administration of paroxetine (20 mg, 5 h before exercise) failed to alter exercise capacity, perceived effort or the response of the determined peripheral hormone markers of central serotonergic activity during prolonged exercise in a warm environment. The present study does not provide any evidence to suggest that an increase in central serotonergic activity has a significant role to play in a centrally mediated fatigue process when prolonged exercise is performed in a warm environment.
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, paroxetine; 
, placebo). Points are slightly displaced on the x-axis to allow variation to be shown. Symbols and bars represent median and range, respectively. A and B denote significant (P < 0.05) differences compared with resting values on the placebo and paroxetine trials, respectively.
