Prompted by the suggested importance of respiration for the pathophysiology of panic disorder, we studied the influence of serotonin reuptake inhibitors (SRIs) as well as other serotonin-modulating compounds on respiration in freely moving rats. The effect on respiration after acute administration of compounds enhancing synaptic levels of serotonin, that is, the serotonin reuptake inhibitors paroxetine and fluoxetine, the serotonin-releasing agents m-chlorophenylpiperazine and d-fenfluramine, and the selective 5-HT1A antagonist WAY-100635, were investigated. All serotonin-releasing substances decreased respiratory rate in unrestrained, awake animals, suggesting the influence of serotonin on respiratory rate under these conditions to be mainly inhibitory. In line with a previous study, rats administered fluoxetine for 23 days or more, on the other hand, displayed an enhanced respiratory rate. The results reinforce the assumption that the effect of subchronic administration of a serotonin reuptake inhibitor on certain serotonin-regulated parameters may be opposite to that obtained after acute administration. We suggest that our observations may be of relevance for the fact that acute administration of SRIs, d-fenfluramine, or m-chlorophenylpiperazine often is anxiogenic in panic disorder patients, and that weeks of administration of an SRI leads to a very effective prevention of panic.