Appetite suppression by commonly used drugs depends on 5-HT receptors but not on 5-HT availability

The widely prescribed appetite suppressants D-fenfluramine and fluoxetine not only decrease feeding and body weight but also increase extracellular brain 5-HT. As central injection of 5-HT also decreases feeding, the drugs are often thought to require an increase of 5-HT at receptors in order to exert their hypophagic effect. However, much evidence now suggests that D-fenfluramine and its metabolite D-norfenfluramine can cause hypophagia by acting directly at unspecified 5-HT receptors and at 5-HT2C receptors, respectively, while fluoxetine may act independently of 5-HT receptors. These hypophagias may involve interference with the hyperphagic action of neuropeptide Y.