Fluoxetine prevents the disruptive effects of fenfluramine on differential-reinforcement-of-low-rate 72-second schedule performance.

This study compared the effects of fenfluramine and fluoxetine on the differential-reinforcement-of-low-rate 72-s schedule of reinforcement. Fluoxetine, a clinically effective antidepressant, increases extracellular serotonin (5-HT) by blocking the uptake of 5-HT after release. Fenfluramine increases extracellular 5-HT through transporter-mediated release (although it also blocks 5-HT uptake). The following characteristics were identified. First, fenfluramine and fluoxetine had two different effects on the differential-reinforcement-of-low-rate 72-s schedule. Fluoxetine had an antidepressant-like effect by increasing reinforcement rate without disrupting the interresponse time distribution. Fenfluramine's effect on the differential-reinforcement-of-low-rate 72-s schedule was not antidepressant-like: it did not increase the reinforcement rate, whereas it did disrupt the interresponse time distribution. Second, when fluoxetine and fenfluramine were given in combination, fluoxetine prevented the disruptive effects of fenfluramine. This result is consistent with fluoxetine's ability to block fenfluramine-induced 5-HT release, and supports the argument that the uptake transporter mediates fenfluramine's effects on both 5-HT release and behavior. Putative behavioral mechanisms (waiting capacity and temporal discrimination) which may mediate the acute effects of fluoxetine are discussed.