Serotonin-mediated central fatigue underlies increased endurance capacity in mice from lines selectively bred for high voluntary wheel running

• Male mice were tested for forced treadmill endurance and voluntary wheel running.
• A serotonin (5-HT1A) agonist or antagonist (varying doses) was administered.
• The effect of each drug on endurance depended on genetic background.
• Effects on wheel running differed from effects on treadmill endurance.
• Results point to genetically determined control of endurance and fatigue.

Serotonin (5-hydroxytryptamine; 5-HT) is implicated in central fatigue, and 5-HT1A pharmaceuticals are known to influence locomotor endurance in both rodents and humans. We studied the effects of a 5-HT1A agonist and antagonist on both forced and voluntary exercise in the same set of mice. This cohort of mice was taken from 4 replicate lines of mice that have been selectively bred for high levels of voluntary wheel running (HR) as compared with 4 non-selected control (C) lines. HR mice run voluntarily on wheels about 3 × as many revolutions per day as compared with C, and have greater endurance during forced treadmill exercise. We hypothesized that drugs targeting serotonin receptors would have differential effects on locomotor behavior of HR and C mice. Subcutaneous injections of a 5-HT1A antagonist (WAY-100,635), a combination of 5-HT1A agonist and a 5-HT1A/1B partial agonist (8-OH-DPAT + pindolol), or physiological saline were given to separate groups of male mice before the start of each of three treadmill trials. The same manipulations were used later during voluntary wheel running on three separate nights. WAY-100,635 decreased treadmill endurance in HR but not C mice (dose by linetype interaction, P = 0.0014). 8-OH-DPAT + pindolol affected treadmill endurance (P < 0.0001) in a dose-dependent manner, with no dose by linetype interaction. Wheel running was reduced in HR but not C mice at the highest dose of 8-OH-DPAT + pindolol (dose by linetype, P = 0.0221), but was not affected by WAY-100,635 treatment. These results provide further evidence that serotonin signaling is an important determinant of performance during both forced and voluntary exercise. Although the elevated wheel running of HR mice does not appear related to alterations in serotonin signaling, their enhanced endurance capacity does. More generally, our results indicate that both forced and voluntary exercise can be affected by an intervention that acts (primarily) centrally.