Increased respiratory dead space causes a serotonin (5-HT) dependent augmentation of the exercise ventilatory response known as short term modulation (STM). Contrary to predictions, 5-HT reuptake inhibition with fluoxetine failed to enhance, and even impaired STM with large dead space volumes (0.4-0.6 L). In this study, we tested the hypotheses that: (1) fluoxetine similarly impairs STM with smaller dead space volumes (0.2 L); whereas (2) acute 5-HT release and reuptake inhibition with fenfluramine would enhance STM. Ventilatory and blood gas measurements were made on five goats (37-58 kg) during rest and exercise, with the mask alone or with increased dead space (0.2 L). STM protocols were performed following chronic fluoxetine (>/=21 days, 1 mg/kg, SQ, SID) and acute fenfluramine administration (1 mg/kg, IV). Following fluoxetine, STM was partially impaired. Fenfluramine had no detectable effects on STM. The data suggest that: (1) chronic fluoxetine diminishes STM, possibly via down-regulation of relevant 5-HT receptors, and (2) drugs that release 5-HT acutely do not enhance STM.