Increased respiratory dead space increases the exercise ventilatory response, a response known as short-term modulation (STM). We hypothesized that STM results from a spinal, serotonin (5-HT)-dependent mechanism. Because 5-HT_1A autoreceptors on caudal brain stem raphe neurons inhibit 5-HT release, we hypothesized that 5-HT_1A-receptor agonists would inhibit, whereas 5-HT_1A-receptor antagonists would enhance, STM. Ventilatory and arterial blood-gas measurements were made at rest and during exercise (4.0-4.5 km/h, 5% grade) in goats with the respiratory mask alone or with increased dead space (0.20-0.25 liter), before and after intravenous administration of the 5-HT_1A-receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 mg/kg) or the antagonist 4-iodo-N-{2-[4-(methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylbenzamide (MPPI; 0.08 mg/kg). 8-OH-DPAT increased the slope of the arterial PCO₂ vs. metabolic CO₂ production relationship and decreased the ventilation vs. metabolic CO₂ production relationship during exercise with increased dead space (not with the mask alone), indicating an impairment of STM. In contrast, MPPI had minimal effects on any measured variable. Although nonspecific effects of 8-OH-DPAT cannot be ruled out, impaired STM is consistent with the hypothesis that STM requires active raphe serotonergic neurons and 5-HT release.