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Why Does Caffeine Delay Exercise-Induced Fatigue?


The popular stimulant blocks adenosine receptors, and is the most likely mechanism of central nervous actions that delay exercise-related fatigue, a new study finds

Consuming caffeine, whether in coffee of soft drinks, has been shown to delay fatigue during prolonged exercise. Studies have shown, for example, that ingesting three to nine mg/kg of caffeine can increase the amount of exercise time to achieve by as much as 50 percent. How caffeine achieves this effect has not been fully determined.

A New Study

No previous research effort has examined the possible direct central nervous system (CNS) effects of caffeine on fatigue during prolonged exercise. Now, a team of researchers from the University of South Carolina has hypothesized that the blockade of adenosine receptors by caffeine may be the most likely mechanism of CNS stimulation and delayed fatigue.

Their theory is based on the fact that adenosine is produced within the body and inhibits neuronal excitability and synapse transmission. Adenosine also inhibits the release of most brain excitatory neurotransmitters, particularly dopamine (DA), and may reduce DA synthesis. Decreases in dopamine (DA), along with increases in 5-HT (serotonin, which is generally associated with behavioral suppression), have been linked to central fatigue during exercise. In addition, adenosine has been shown to reduce arousal, induce sleep, and suppress spontaneous activity, which are all behaviors associated with increases in 5-HT.

The researchers’ hypothesis is the foundation of a new study to determine the effects of intracerebroventricular injection of caffeine and the adenosine A1 and A2 receptor agonist 5’-N-ethylcarboxamidoadenosine (NECA) on treadmill run time to fatigue in rats. NECA was chosen for the study because caffeine is a nonselective adenosine receptor antagonist, and it is not known which of the four subtypes of adenosine receptors may be involved in an effect of caffeine on fatigue. However, A2b and A3 receptors are relatively less active than A1 and A2a receptors under normal physiological conditions. If the researchers were correct, the CNS administration of caffeine will increase run time to fatigue, whereas NECA will reduce run time to fatigue. Furthermore, pretreatment with caffeine before NECA will weaken the fatigue-inducing effects of NECA.

The authors of “Central Nervous System Effects of Caffeine and Adenosine on Fatigue,” are J. Mark Davis, Zuowei Zhao, Howard S. Stock, Kristen A. Mehl, James Buggy, and Gregory A. Hand, all from the Schools of Public Health and Medicine, University of South Carolina, Columbia, SC. Their findings appear in the February 2003 edition of the American Journal of Physiology –Regulatory, Integrative and Comparative Physiology. The journal is one of 14 peer-reviewed publications produced monthly by the American Physiological Society (APS).


Male Wistar rats, five weeks old and weighing 200-250 grams, were used in this study, and randomly assigned to intracerebroventricular or intraperitoneal injection groups. Rats were given two weeks of treadmill acclimation of running for 15 minutes a day. The treadmill speed was slowly increased from eight meters a minute, 7.5 percent grade at the beginning, progressing to 20 meters a minute at the end of the acclimation period. Gentle hand prodding and mild electric shock were combined to encourage the animals to run throughout the study.

After the first two weeks of acclimation, rats assigned to the intracerebroventricular group were anesthetized with pentobarbital sodium, and tubes were implanted bilaterally into the lateral ventricles. After seven days of recovery from surgery, the rats were again acclimated to treadmill running for another one to two weeks, until they were able to run easily for at least 15 minutes per day for 5 consecutive days at a speed of 20 meters a minute at a 7.5 percent grade. Animals that were unable to run at that pace were excluded.

Four drug treatments were used in the study: NECA, caffeine, caffeine plus NECA, and a vehicle solution (Normosol-R). The vehicle solution has been used as a control solution in other studies involving intracerebroventricular infusions of drugs and tissue microdialysis. In the CNS groups (n = 10), each rat was injected intracerebroventricularly with one of the four drugs (NECA, caffeine, caffeine plus NECA, or vehicle) in one testing session. The other drugs were then given in successive testing sessions at one-week intervals to allow full recovery from the exercise bout and washout of the drugs. On two days during the recovery period, all rats were exercised for 15 minutes to maintain acclimation to the treadmill protocol. All rats received all four-drug treatments in a randomized and counterbalanced design to minimize possible order effects.


The major findings of this study revealed that:

  • CNS administration of caffeine at a dose of 200 µg/rat (0.6 mg/kg), which is much less than the effective dose given peripherally (6 mg/kg), does increase treadmill run time to fatigue in rats by approximately 60 percent;

  • the same dose of caffeine given peripherally (intraperitoneally) is ineffective;

  • the results supported the researchers’ hypothesis that intracerebroventricular CNS administration of the selective adenosine A1 and A2 receptor agonist NECA significantly reduced run time to fatigue, whereas intracerebroventricular caffeine increased run time to fatigue;

  • inhibitory effects of NECA on run time to fatigue were also reversed by intracerebroventricular pretreatment with caffeine, suggesting that the ergogenic effects of intracerebroventricular caffeine are mediated through blockade of the adenosine receptors;

  • CNS administration of the adenosine receptor agonist NECA inhibited treadmill run time to fatigue and spontaneous locomotor activity in rats;

  • pretreatment with caffeine blocked the inhibitory effects of NECA on exercise performance, although not on spontaneous behavioral activity;

  • peripheral (intraperitoneal) administration of the same drugs at the same doses had no effect on treadmill run time to fatigue.


These results indicate that caffeine can act specifically within the CNS to delay fatigue, at least in part by blocking adenosine receptors. Because caffeine easily crosses the BBB, these results also suggest that the CNS also plays an important role in the ergogenic effect of caffeine ingestion.

The precise independent contribution of caffeine at the central (behavioral) and peripheral (metabolic) levels awaits further research. The researchers argue that some interaction at both levels is likely.

Source: February 2003 edition of the American Journal of Physiology— Regulatory, Integrative and Comparative Physiology


The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

Donna Krupa | APS
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