Hypothalamic neuropeptide Y (NPY) and 5-hydroxytryptamine (5-HT) may interact to regulate food intake. This study investigated the effects of the 5-HT reuptake blocker and secretagogue D-fenfluramine (D-FEN) on preproNPY mRNA abundance in the hypothalamic arcuate nucleus (ARC) of free-feeding and food-deprived (FD) rats in two treatment regimens. ARC preproNPY mRNA levels were significantly increased in FD rats, to the same extent as in combined FD/D-FEN animals. D-FEN treatments producing different-sized reductions in food intake (and body weight) produced corresponding changes in ARC preproNPY mRNA abundance. These findings suggest that ARC preproNPY mRNA levels are not directly altered by D-FEN, and that D-FEN-induced anorexia does not involve effects on the hypothalamic NPY system at the level of NPY gene transcription.