Fluoxetine (Prozac) inhibits serotonin (5-HT) re-uptake. thereby enhancing serotonergic effects. Since serotonin is known to affect ventilation in a variety of circumstances, we investigated the effects of chronic serotonin re-uptake inhibition with fluoxetine on selected ventilatory responses including: (1) eupnea; (2) the hypercapnic ventilatory response at rest; (3) the exercise ventilatory response and (4) repeated trials of hypercapnic exercise. Ventilatory and arterial blood gases were measured in goats (n = 5) at rest, during steady-state treadmill exercise, and during successive rest/exercise trials with increased respiratory dead space (0.4-0.6 L). Fluoxetine was administered (> or = 4 weeks, 1 mg/kg, SQ, SID) and protocols were repeated. Following fluoxetine, PaCO2 was increased in most conditions studied; however, no differences were seen in exercise PaCO2 regulation or ventilatory responses pre- versus post-fluoxetine. We conclude that chronic fluoxetine slightly depresses respiratory control at rest, but, has minimal effects during exercise or with mild hypercapnia during rest or exercise in goats.