During and after maximal exercise there is a 15-30 % decrease in the metabolic uptake ratio (O(2)/[glucose + 1/2 lactate]) and a net lactate uptake by the human brain. This study evaluated if this cerebral metabolic uptake ratio is influenced by the intent to exercise, and whether a change could be explained by substrates other than glucose and lactate. The arterial-internal jugular venous differences (a-v difference) for O(2), glucose and lactate as well as for glutamate, glutamine, alanine, glycerol and free fatty acids were evaluated in 10 healthy human subjects in response to cycling. However, the a-v difference for the amino acids and glycerol did not change significantly, and there was only a minimal increase in the a-v difference for free fatty acids after maximal exercise. After maximal exercise the metabolic uptake ratio of the brain decreased from 6.1 +/- 0.5 (mean +/- S.E.M.) at rest to 3.7 +/- 0.2 in the first minutes of the recovery (P < 0.01). Submaximal exercise did not change the uptake ratio significantly. Yet, in a second experiment, when submaximal exercise required a maximal effort due to partial neuromuscular blockade, the ratio decreased and remained low (4.9 +/- 0.2) in the early recovery (n = 10; P < 0.05). The results indicate that glucose and lactate uptake by the brain are increased out of proportion to O(2) when the brain is activated by exhaustive exercise, and that such metabolic changes are influenced by the will to exercise. We speculate that the uptake ratio for the brain may serve as a metabolic indicator of 'central fatigue'.