8* 5.1 ± 2.1* [Pyruvate] (μmol·L-) Control 157 ± 33 230 ± 46 218 ± 50 221 ± 49 224 ± 51 228 ± 48 234 ± 53 254 ± 61   F 159 ± 33 235 ± 49

223 ± 58§ 218 ± 53 212 ± 57 215 ± 44 216 ± 47 219 ± 46   FC 163 ± 41 256 ± 52 252 ± 58* 250 ± 57* 245 ± 57* 237 ± 63 239 ± 61 234 ± 51 Values are presented as the mean ± SD *: Indicates a significant difference from the F trial at the same time-point. §: Indicates a significant difference within the trials compared with the 15 min time-point. Figure 2 Plasma free-Trp:LNAA ratio (bottom panel), free-Trp:Tyr ratio (middle panel) and plasma free-Trp (top panel). *: indicates a significant difference between the F (white dots) and the FC (black dots) trials. §: indicates significant differences within the trials compared with the 15 min time-point. The dash line indicates the Control trial. Values are Selonsertib presented as the mean ± SD. Figure 3 Plasma prolactin Tucidinostat responses between the F (white dots) and the FC (black

dots) trials. §: indicates significant differences within the trials compared with the 15 min time-point. The dash line indicates the Control trial. Values are presented as the mean ± SD. Figure 4 Plasma FFA responses. *: indicates a significant difference between the F (white dots) and the FC (black dots) trials. §: indicates significant differences within the trials compared with the 15 min time-point. The dash line indicates the Control trial. Values are presented Cyclin-dependent kinase 3 as the mean ± SD. Reported side effects Four out of the ten subjects experienced slight gastrointestinal discomfort; three following the high fat meal with caffeine and one following the high fat meal alone. One subject experienced more severe side effects following the high fat

meal and caffeine ingestion 30 min following exercise. These effects included loss of consciousness, dizziness, abdominal pain, nausea and vomiting. These effects disappeared shortly after the experience. Discussion The present study examined the relationship between the putative modulators and indices of brain serotonergic and dopaminergic function, effort perception and endurance exercise performance in a relatively cold (10°C) environment following caffeine co-ingestion with a high fat meal in well-trained humans. The results presented here do not support any significant Vactosertib clinical trial involvement of the putative modulators of brain serotonergic and dopaminergic function in the exercise fatigue process during submaximal constant-load exercise at low ambient temperatures. This lack of involvement of the putative modulators of ‘central fatigue’ was observed despite a significant reduction in effort perception following caffeine ingestion. It is difficult however, to explain why the subjects in the present experiment perceived it easier to exercise with caffeine than without, particularly when one considers the accompanying elevation in blood [lactate], O2, and E that typically would be expected to augment, rather than attenuate effort perception [23].