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Subjects were exercising at approximately 75% of their maximal ... Email: [email protected] .... visits subjects wore either a 7mg transdermal nicotine.
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Exp Physiol 91.4 pp 705–713

Experimental Physiology

Effect of transdermal nicotine administration on exercise endurance in men Toby M¨undel1 and David A. Jones1,2 1

Human Performance Laboratory, School of Sport and Exercise Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Institute for Biophysical and Clinical Research into Human Movement, Manchester Metropolitan University, Hassall Road, Alsager, Cheshire ST7 2HL, UK 2

Nicotine is widely reported to increase alertness, improve co-ordination and enhance cognitive performance; however, to our knowledge there have been no attempts to replicate these findings in relation to exercise endurance. The purpose of this study was to determine the effects nicotine might have on cycling endurance, perception of exertion and a range of physiological variables. With local ethics committee approval and having obtained informed consent, 12 healthy, nonsmoking men (22 ± 3 years; maximal O2 uptake, 56 ± 6 ml kg– 1 min– 1 , mean ± S.D.) cycled to exhaustion at 18◦ C and 65% of their peak aerobic power, wearing either a 7 mg transdermal nicotine patch (NIC) or a colour-matched placebo (PLA) in a randomized cross-over design; water was available ad libitum. Subjects were exercising at approximately 75% of their maximal O2 uptake with no differences in cadence between trials. Ten out of 12 subjects cycled for longer with NIC administration, and this resulted in a significant 17 ± 7% improvement in performance (P < 0.05). No differences were observed for perceived exertion, heart rate or ventilation. There were no differences in concentrations of plasma glucose, lactate or circulating fatty acids. In the absence of any effect on peripheral markers, we conclude that nicotine prolongs endurance by a central mechanism. Possible modes of action are suggested. (Received 31 January 2006; accepted after revision 10 April 2006; first published online 20 April 2006) Corresponding author T. M¨undel: School of Sport and Exercise Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Email: [email protected]

The use of stimulants is widespread owing to their properties of allaying fatigue and enhancing attention. Of the well-known stimulants, amphetamine and cocaine use is marginal compared to caffeine and nicotine, which are considered as the most widely consumed psychostimulants in the world, with more than 80% of the world population consuming caffeine and/or nicotine on a daily basis (Boutrel & Koob, 2004). There have been reports of amphetamine sulphate delaying fatigue during repeated bouts of exercise (Borg et al. 1972) and of caffeine improving exercise capacity (Pasman et al. 1995) as well as reducing perceived exertion (Cole et al. 1996); however, research on nicotine has concentrated on the pharmacodynamics of the drug and improving smoking cessation, with no published studies having examined the effects of nicotine on exercise endurance/capacity. Nicotine administration during light physical activity has been shown to increase heart rate and blood pressure with no effect on ventilation (Perkins et al. 1989; Turner & McNicol, 1993), as well as having no effect on perceived  C 2006 The Authors. Journal compilation  C 2006 The Physiological Society

exertion (Perkins et al. 1991); however, protocols included smokers, sedentary subjects and work rates of cycling between 30 and 150 W for a maximum of 15 min. Van Duser & Raven (1992) observed a significant increase in heart rate and a decrease in stroke volume together with an increase in blood lactate at rest and during treadmill exercise at 60 and 85% maximal O2 uptake (V˙ O2 max ) with oral smokeless tobacco (OST), compared to a placebo. The authors concluded that OST-induced increases in plasma nicotine concentrations augment anaerobic energy production and suggest a nicotine-induced sympathetic stimulation of the heart (Van Duser & Raven, 1992). Nicotine, 3-(1-methyl-2-pyrrolidinyl)pyridine, is a potent activator of the sympathetic nervous system, and in healthy humans increases heart rate and blood pressure (Cryer et al. 1976), cardiac stroke volume and output (Irving & Yamamoto, 1963) and coronary blood flow (Bargeron et al. 1957). Nicotine also causes cutaneous vasoconstriction (Freund & Ward, 1960), associated with a decrease in skin temperature, systemic venoconstriction DOI: 10.1113/expphysiol.2006.033373

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(Eckstein & Horsley, 1960) and increased muscle blood flow (Rottenstein et al. 1960). Circulating levels of noradrenaline and adrenaline increase after nicotine consumption, as do concentrations of free fatty acids, glycerol and lactate (Cryer et al. 1976). Although the cardiovascular and metabolic effects of nicotine are pronounced, it is likely that during moderate-intensity or prolonged exercise when sympathetic output is high, the peripheral effects of nicotine may be attenuated. Smoking and administration of nicotine are often associated with increased alertness, improved coordination and positive mood changes. It is likely that cortical arousal is a result of nicotine directly stimulating cholinergic neurotransmission in the basal forebrain (Boutrel & Koob, 2004). Nicotine has also been shown to increase dopamine release in the striatum and nucleus accumbens, the reward centre of the brain, and this effect is mediated by nicotinic acetylcholine receptors (Clarke et al. 1988; Reavill & Stolerman, 1990; O’Neill et al. 1991). It is therefore likely that administration of nicotine may enhance motivation during prolonged exercise owing to an increased release of dopamine, possibly involving similar pathways to those suggested for the central actions of caffeine. Bridge et al. (2000) demonstrated that caffeine supplementation improved exercise endurance by ∼20% and significantly reduced the perception of exertion whilst cycling at 18 and 35◦ C, compared to a placebo. Since no effects were observed on indicators of peripheral metabolic stress, it was concluded that the action was central and, furthermore, since there was no effect on the release of prolactin, it was concluded that caffeine may be acting on central pathways other than those in the hypothalamus which are sensitive to temperature. Despite the wealth of literature describing the effects of caffeine on exercise performance, there have been no attempts to replicate these findings with nicotine. The aim in this study was therefore to determine the effects nicotine might have on exercise endurance, perception of exertion and a range of physiological variables. The hypothesis of the present study was that nicotine administration would improve endurance capacity and reduce perception of exertion in a similar way to that observed by Bridge et al. (2000) after caffeine consumption. Methods General design

All tests were carried out on an electrically braked cycle ergometer (Excalibur Lode, Groningen, Netherlands) set in the pedal rate independent mode. The protocol consisted of four visits. Visit 1 was an incremental exercise test to determine V˙ O2 max , maximal aerobic power

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output (W max ) and maximal heart rate (HRmax ). Visits 2– 4 involved exercising at 65% W max until exhaustion at standard ambient temperature of 18–22◦ C and 50– 60% relative humidity (RH). Visit 2 served to familiarize subjects with the protocol and equipment, thereby minimizing any practice effect. For the remaining two visits subjects wore either a 7 mg transdermal nicotine patch (NIC) or a colour-matched placebo (PLA). The study was carried out in a counterbalanced, randomized fashion with subjects blind to the purpose of the study. Subjects

Twelve healthy males volunteered their written informed consent to participate in the study. The study was performed according to the Declaration of Helsinki and was approved by the Local Ethics Committee. The subjects’ physical characteristics were (means ± s.d.): age, 22 ± 3 years; body mass, 77 ± 13 kg; height, 181 ± 8 cm; V˙ O2 max , 56 ± 6 ml kg−1 min−1 , W max , 297 ± 36 W; HRmax , 191 ± 9 beats min−1 . All subjects were non-smokers, familiar with cycle ergometry at this intensity and had completed the School’s General Health Questionnaire. Experimental design Visit 1. Subjects performed an incremental exercise test to volitional fatigue at a self-selected cadence. The seat position, handlebar height and orientation were adjusted for each subject, and the same settings were used for all subsequent rides. The initial workload was 95 W, which was increased by 35 W every 3 min until fatigue. Heart rate (HR) was monitored continuously (Polar Accurex Plus, Polar Electro Oy, Kempele, Finland) as were O2 and CO2 (Oxycon Pro, Jaeger, W¨urzburg, Germany). The test was considered maximal if one of the following criteria was met: (1) final HR was within 10% of predicted maximum; (2) a clear plateau in oxygen uptake was seen; or (3) respiratory exchange ratio was equal to, or above, 1.10. Maximal aerobic power output (W max ) was determined using the equation of Kuipers et al. (1985):

Wmax = Wfinal + (t × W )/T where W final (in W) is the power of the last completed stage, t (in s) is the time completed in the final stage, T (in s) is the duration of each stage and W (in W) is the workload increment. Visits 2–4. Subjects were advised to consume a diet high in carbohydrates in the 24 h period prior to each visit to minimize differences and ensure adequate muscle glycogen concentrations. Subjects were asked to record their diet in the 24 h period before the second visit and instructed to follow the same diet before each subsequent visit. Subjects arrived at the laboratory by 08.00 h, having fasted  C 2006 The Authors. Journal compilation  C 2006 The Physiological Society

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Nicotine and exercise endurance

since 22.00 h the previous evening. Subjects were asked to abstain from exercise, alcohol and caffeine for the 24 h preceding the visit. A cannula (20 gauge, Venflon, Oxford, UK) was inserted into an antecubital vein and kept patent with saline (Baxter, Norfolk, UK) during the test. Subjects were then asked to empty their bladder before being weighed nude. Subjects rested seated for 40 min, after which a resting blood sample was taken. Subjects were given a bolus of water (8 ml (kg body weight)−1 ) and started to exercise at a constant work rate of 65% W max until exhaustion. Subjects wore shorts and T-shirt. A fan was used to circulate the air; this was set at ∼0.5 m s−1 and in the same position/distance for all trials. In the event of a subject needing to urinate during the test, the subject stopped pedalling and passed urine into a container whilst remaining in the laboratory. Water was available ad libitum, and exercise was stopped at the subject’s volition. Following exercise, the subject was weighed nude to allow for measurement of sweat loss; this was corrected for urinary loss (collected throughout the ride), respiratory (Snellen, 1966) and metabolic loss (Mitchell et al. 1972), fluid intake and quantity of blood drawn, and divided by time to give an average sweat rate over the entire period of exercise. Nicotine administration

For the NIC trial, the subject was given a clear, 7 mg nicotine patch (7 mg (24 h)−1 ; NiQuitin CQ Clear, GlaxoSmithKline, Uxbridge, UK) with the instructions to apply the patch onto the left deltoid muscle at 22.00 h on the evening preceding the test. For the PLA trial, a clear first aid plaster (Elastoplast, Birmingham, UK) was applied to the left deltoid by the investigator when the subject entered the laboratory. In order to keep the experiment singleblind, subjects were informed that the aim of the study was to look at differences in timing of nicotine administration on performance. Blood collection and analyses

Venous blood samples (8 ml) were collected into prechilled EDTA-containing tubes at rest, at 10 min intervals throughout the ride and at the point of fatigue. One millilitre of blood was separated and analysed for haemoglobin and haematocrit. The remaining whole blood was centrifuged at 2300 g for 10 min at 4◦ C and the plasma separated and stored at −70◦ C until further analysis. Haemoglobin concentration was measured using a Coulter® AC ·T diffTM Analyser (Beckman Coulter Inc., Miami, FL, USA), and haematocrit was measured in triplicate by centrifugation. Changes in plasma volume were calculated from haemoglobin concentrations and haematocrit values using the equations of Dill & Costill (1974). Blood glucose and lactate concentrations were  C 2006 The Authors. Journal compilation  C 2006 The Physiological Society

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determined enzymatically (Sigma Diagnostics, Dorset, UK), as were levels of circulating fatty acids (Wako Chemicals GmbH, Neuss, Germany) on a semi-automatic analyser (Cobas Bio, Basel, Switzerland). Prolactin and growth hormone concentrations were measured using radioimmunoassays (Skybio Ltd, Bedford, UK). Average inter- and intra-assay coefficients of variations were 5.9 and 2.7%, respectively. All hormone analyses from a single subject were carried out in the same assay batch. Plasma cotinine levels were used to detect successful systemic administration of nicotine and analysed using a commercially available enzyme-linked immunosorbent assay kit (Cozart, Abingdon, UK). Levels of cotinine for NIC were accepted at ≥ 25 ng ml−1 and for PLA < 25 ng ml−1 . Gas, temperature and HR measurement

Breath-by-breath measurements were performed throughout exercise using an on-line automated gas analysis system (Oxycon Pro). The volume sensor was calibrated using a 3 l calibration syringe, and the gas analysers were calibrated using a 5.03% CO2 – 94.97% N2 gas mixture. Gas samples were collected for 3 min intervals, every 10 min, to determine expiratory minute ventilation (V˙ E ), O2 consumption rate ( V˙ O2 ) and rate of CO2 production (V˙ CO2 ), from which the respiratory exchange ratio (RER) was calculated. Ambient temperature during each ride was measured using a wet and dry bulb mercury thermometer (Brannan, Cumbria, UK), and RH calculated from wet and dry bulb thermometer differential. Heart rate was recorded continuously throughout by telemetry (Polar Accurex Plus). Perceptual measurement

All measurements were taken every 10 min. Global rating of perceived exertion (RPE) was recorded using the 15point Borg scale (Borg, 1982). Separate RPE for breathing (RPEbre ) and legs (RPEleg ) were recorded using the CR-10 scale to assess the extent that central (cardiopulmonary) and local (muscular) signals contribute to global RPE (Noble et al. 1983). Data and statistical analyses

All statistical analyses were carried out with the use of the SPSS package, version 12.0 (SPSS Inc., Chicago, IL, USA). Data were tested for approximation to a normal distribution. Exercise data were analysed up to 40 min and at fatigue to include maximum number of subjects and were analysed using a two-way (time × trial) repeated measures ANOVA with a Bonferroni confidence interval adjustment when comparing main effects. Values from ANOVA were assessed for sphericity and if necessary

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corrected using the Huynh-Feldt method. Following a significant F test, pairwise comparisons were identified using Tukey’s honestly significant difference (HSD) post hoc procedure. For differences in time to fatigue, and in drink and sweat rates, Student’s paired t tests were used. Data are reported as means ± s.e.m., unless otherwise stated. Statistical significance was accepted at P < 0.05. Statistical analysis was performed on n = 12, unless otherwise stated.

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Results Exercise capacity and perceived exertion

Subjects were cycling at the same intensity for both trials (77 ± 3% V˙ O2 max ). Cadence dropped from 91 ± 3 r.p.m. at 10 min to 77 ± 4 r.p.m. at fatigue during PLA (P < 0.001). The corresponding values for NIC were 95 ± 2 and 79 ± 4 r.p.m., respectively (P < 0.001) with no differences between trials. Ten out of 12 subjects cycled for longer during the NIC trial (Fig. 1); exercise times were 62 ± 6 min for the PLA trial and 70 ± 7 min for the NIC trial, a significant 17% increase (P < 0.05). Global RPE is shown in Fig. 2. Global RPE increased significantly during both trials (P < 0.001), from 12.4 ± 0.4 at 10 min to 18.2 ± 0.3 at fatigue for PLA, and from 12.0 ± 0.2 at 10 min to 18.5 ± 0.3 at fatigue for NIC; however, no differences were observed between trials. Nicotine had no effect on ratings of RPEbre , which increased significantly during exercise, with values reaching 6.4 ± 0.6 and 7.0 ± 0.6 for PLA and NIC, respectively (P < 0.001). A main effect of time (P < 0.001) but not trial was observed for RPEleg , with values increasing during exercise for both trials before reaching 8.8 ± 0.4 for PLA and 9.5 ± 0.3 for NIC at fatigue.

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Figure 1. Exercise times for individual subjects during placebo and nicotine trials

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The heart rate response to exercise is shown in Fig. 3. Heart rate increased steadily during exercise from 145 ± 3 beats min−1 after 5 min to 167 ± 3 beats min−1 at fatigue for PLA, and from 144 ± 3 beats min−1 at 5 min to 166 ± 3 beats min−1 at fatigue for NIC, a significant

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Exercise Time (min) Figure 2. Perceived exertion (Borg scale) during exercise for PLA (•) and NIC () Rightmost data points indicate values at fatigue. ∗ Denotes significant difference from 10 min value in both trials, n = 12.

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Exercise Time (min) Figure 3. Heart rate response during exercise for PLA (•) and NIC () Rightmost data points indicate values at fatigue. ∗ Denotes significant difference from 5 min value in both trials, n = 12.  C 2006 The Authors. Journal compilation  C 2006 The Physiological Society

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Figure 4. Minute ventilation (A) and O2 consumption (B) during exercise for PLA (•) and NIC () Rightmost data points indicate values at fatigue. ∗ Denotes significant difference from 10 min value in both trials, n = 12.

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cardiac drift of 22 beats min−1 in both trials (P < 0.001); however, NIC had no effect compared to PLA. There were no differences in any of the respiratory variables between trials ( V˙ E , % V˙ O2 max and RER), which suggests that the energy consumption, gross efficiency and relative rates of fuel oxidation were not altered by NIC. Minute ventilation (Fig. 4A) increased steadily during exercise in both trials (P < 0.001), and there was a tendency for NIC to be ∼3 l min−1 higher than PLA, but this difference was not significant (P = 0.09). Oxygen consumption (Fig. 4B) increased during the first 30 min of exercise in both trials (P = 0.001), with values after 10 min exercise of 3.18 ± 0.12 (PLA) and 3.13 ± 0.11 l min−1 (NIC). The corresponding values at fatigue were 3.34 ± 0.16 (PLA) and 3.34 ± 0.09 l min−1 (NIC); no effects of trial were observed. There was no difference in fuel oxidation between trials but there was a shift to a greater fat oxidation towards the end of exercise (Fig. 5; P < 0.001), an expected observation because subjects consumed only water. As depicted in Fig. 6, there was no difference between trials in the amount of water consumed, with a drink rate of

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0.7 ± 0.1 l h−1 for PLA and NIC. There was a tendency for sweat rate to be lower for NIC (0.9 ± 0.1 l h−1 , compared to 1.1 ± 0.1 l h−1 for PLA); however, this was not significant (P = 0.2). Plasma metabolite and hormonal responses

Plasma cotinine levels were detected in only four subjects for PLA, with all values < 10 ng ml−1 . Blood cotinine levels of ≥ 50 ng ml1 were detected in eight subjects for NIC, and for the remaining four, levels ranged between 37 and 49 ng ml−1 . Concentrations of plasma lactate increased significantly by 10 min from resting values of ∼1 mmol l−1 (P < 0.001) but stabilized thereafter and did not change during exercise or between trials (PLA, 4.1 ± 0.5 mmol l−1 ; NIC, 3.9 ± 0.5 mmol l−1 ). Plasma glucose (Fig. 7) was stable during exercise, with a tendency for NIC to be higher during the second half of exercise when compared to PLA (4.5 ± 0.2 versus 4.3 ± 0.3 mmol l−1 , respectively); however, this was not significant (P = 0.18). Circulating free fatty acids (FFA; Fig. 8) were suppressed after 10 min of exercise in both trials, increasing thereafter until

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Exercise Time (min) Figure 5. Respiratory exchange ratio (RER) for PLA (•) and NIC () Rightmost data points indicate values at fatigue. ∗ Denotes significant difference from 10 min value in both trials, n = 12.  C 2006 The Authors. Journal compilation  C 2006 The Physiological Society

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Figure 6. Sweat rate () and water consumption () for placebo and nicotine n = 12.

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Table 1. Plasma growth hormone and prolactin concentrations for PLA and NIC PLA

NIC

l−1 )

Growth hormone (mU Rest 9 (7) Fatigue 137 (29)∗

5 (3) 184 (20)∗

Prolactin (mU l−1 ) Rest 355 (69) Fatigue 679 (139)∗

239 (23) 547 (132)∗

Values are means (S.E.M.), n = 12. ∗ Denotes significant difference from rest value.

fatigue (P < 0.001), with values of 315 ± 33 (PLA) and 316 ± 28 μmol l−1 (NIC). Free fatty acids tended to be lower for NIC but this was not statistically significant (P = 0.28). Concentrations of prolactin and growth hormone were similar at rest and had increased significantly by the end of exercise; however, no differences were observed between trials (Table 1). Plasma volume changes were minimal and similar in both trials (PLA, −13 ± 3%; NIC, −10 ± 2%; P = 0.22), indicating that differences between the trials in blood metabolites or hormones were not a consequence of haemoconcentration. Discussion The results reported here confirm that nicotine administration during moderate-intensity exercise delays fatigue, with a significant improvement of 17 ± 7% in time to exhaustion. This observation is similar to observations of the effects of caffeine supplementation (Pasman et al. 1995; Bridge et al. 2000).

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Despite the widespread use of nicotine and general acceptance that it promotes many of the characteristics provided by other stimulants, such as caffeine, cocaine and amphetamines, there has been no quantitative research about its benefits on endurance capacity during moderate and prolonged exercise, where the progressive development of central fatigue is believed to be a contributing factor in maintaining motivation. Whilst the present observation of a ∼17% improvement in exercise duration may be the first demonstration of the efficacy of nicotine, others have shown improvements of this magnitude at a similar intensity for caffeine (Pasman et al. 1995; Graham & Spriet, 1995; Bridge et al. 2000), as well as amphetamine sulphate ingestion, which delays fatigue and improves time to exhaustion during short, intense bouts of exercise of < 10 min (Borg et al. 1972; Chandler & Blair, 1980). It is likely that, as for caffeine, the maximal benefits of nicotine will be seen with exercise of 70–80% maximal aerobic capacity; depletion of muscle glycogen is likely to be the limiting factor during exercise below this intensity, whilst at higher intensities, cardiovascular and respiratory limitations, combined with peripheral muscle fatigue, will predominate. There was no evidence in the present study that nicotine altered cardiovascular or respiratory parameters. Although a significant cardiac drift was observed, there were no differences between trials for heart rate during exercise. Increases of 11 and 6 beats min−1 have been observed during exercise with similar (0.5–2.0 mg; Perkins et al. 1991) or higher (4 mg; Turner & McNicol, 1993) doses of nicotine administered, respectively. However, exercise duration was only 9 min in the former study and workload was limited to 30 or 60 W in the latter study. When

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Exercise Time (min) Figure 8. Free fatty acid (FFA) concentration during exercise for PLA (•) and NIC () Rightmost data points indicate values at fatigue. ∗ Denotes significant difference from 10 min value in both trials, n = 12.  C 2006 The Authors. Journal compilation  C 2006 The Physiological Society

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Nicotine and exercise endurance

compared to a placebo, Van Duser & Raven (1992) observed significant increases in heart rate, ranging from 18 beats min−1 at rest to 6 beats min−1 at 85% V˙ O2 max during treadmill exercise following oral smokeless tobacco (OST) use. The authors also reported a significant decrease in stroke volume, ranging from 15 ml per beat at rest to 7 ml per beat at 60% V˙ O2 max , with no change in cardiac output between trials. In the present study, subjects were cycling at over 75% V˙ O2 max and an equivalent work rate of 75% HRmax (after 10 min) to 88% HRmax (at fatigue). It is therefore likely that any nicotine-induced sympathetic stimulation of the heart was masked by the strong sympathetic output during the ∼1 h of cycling. Although there was a tendency for V˙ E to be 3 l min−1 higher during NIC trials, this is more likely to be due to a proportionally similar increase in cadence during the first 30 min (∼4 r.p.m.) than a consequence of nicotine administration; neither difference was significant. Furthermore, mean absolute (PLA, 3.21 ± 0.16 l min−1 ; NIC, 3.25 ± 0.09 l min−1 ) and relative V˙ O2 (PLA, 77 ± 3% V˙ O2 max ; NIC, 77 ± 3% V˙ O2 max ) were not altered by administration of nicotine. There was a tendency for sweat rate to be lower for NIC (Fig. 6), and this is most probably due to cutaneous vasoconstriction in response to higher circulating catecholamines (Smits et al. 1989); however, this difference was not significant. There was no evidence in the present study that nicotine altered substrate metabolism in any way that would lead to greater endurance, with concentrations of lactate and glucose stable during exercise and no differences between trials. This is in contrast to the results reported by Van Duser & Raven (1992), who observed higher concentrations of lactate with OST use and postulated that nicotine would reduce the regional blood flow to the working muscles as a result of sympathetic vasoconstriction. However, administration of nicotine was acute and immediately before exercise and, since the protocol consisted of both steady-state and incremental treadmill exercises, it is not possible to compare these results directly. In the present study, during NIC, subjects had slightly lower levels of FFA compared to PLA when first reporting to the laboratory (PLA, 191 ± 18 μmol l−1 ; NIC, 238 ± 27 μmol l−1 ), and this trend continued during the first 40 min of exercise (PLA, 216 ± 12 μmol l−1 ; NIC, 175 ± 9 μmol l−1 ), but statistical significance was not reached. These findings are a little puzzling, since previous studies at rest have found FFA to be higher following acute nicotine administration (Mjos, 1988; Andersson et al. 1993), whilst similar studies with caffeine supplementation during exercise have also shown levels of FFA to increase when compared to a placebo (Graham et al. 1998; Bridge et al. 2000). Nevertheless, although circulating fatty acid levels were lower during the present study, there were no changes in blood glucose or lactate, nor in V˙ O2 or RER, indicating that fuel oxidation rates were the same in both trials.  C 2006 The Authors. Journal compilation  C 2006 The Physiological Society

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Since nicotine had no effect on peripheral mechanisms involving the cardiovascular and respiratory systems or on metabolic pathways governing fuel oxidation, attention should be focused on the central actions of nicotine. Studies in rodents have shown that nicotine activates central dopamine systems; nicotine administration leads to increased dopamine cell firing in the ventral tegmental area (Corrigall et al. 1994) and increased dopamine release in the nucleus accumbens (Pontieri et al. 1996), actions which are thought to be critical to the reinforcing properties of nicotine as an addictive drug. Studies on humans are limited, since dopamine cannot be measured directly. Brody et al. (2004) used positron emission tomography (PET) to identify [11 C]raclopride binding potential, an indirect measure of dopamine release, in smokers. They observed that smokers who smoked a cigarette during PET scanning had greater reductions in [11 C]raclopride binding potential than those who underwent the same procedure but did not smoke. These differences were in the ventral striatum, including the nucleus accumbens and, as such, Brody and colleagues were the first to demonstrate dopamine release (indirectly) in response to smoking. Nicotine has a very similar chemical structure to acetylcholine, and it is has been shown that the nicotine-induced mesolimbic dopamine release is mediated by nicotinic receptors (α 4 nicotinic acetylcholine receptors) on dopaminergic neurones, also requiring the activation of D1 and D2 dopamine receptors (Reavill & Stolerman, 1990; O’Neill et al. 1991; Marubio et al. 2003), and activity of dopamine pathways has been suggested to be associated with improved endurance exercise performance (Davis & Bailey, 1997; Bridge et al. 2003). A surprising finding was that nicotine did not alter the perception of effort (Borg scale) associated with progressive fatigue (Fig. 2). This is in contrast to studies with caffeine, where supplementation caused a significant reduction in perceived exertion from the start of exercise (Cole et al. 1996; Bridge et al. 2000). An explanation may be found when considering tolerance and sensitivity to nicotine. All subjects commented on the ‘side-effects’ they experienced overnight after applying the nicotine patch; these included increased heart rate and reduced appetite, headaches and nausea, restless sleep and vivid/bizarre dreams and feelings of having a hangover when they arrived for testing; most subjects reported that these symptoms disappeared once they started exercising. These symptoms are common and similar to those experienced by people deprived of nicotine, and indeed caffeine when their habitual intake is high. While the majority of society has a relatively steady intake of caffeine in the form of tea, coffee, certain soft drinks, nuts and chocolate and therefore a reasonable tolerance to caffeine, the same cannot be said about nicotine. It is only smokers or those trying to give up with the use of aids that have a tolerance to

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