Dexfenfluramine (dF) and dexnorfenfluramine (dNF), its metabolite, are anorectic agents that release serotonin (5-HT) and may have a direct postsynaptic action. The effects on the anorectic effects of dF and dNF of either acute (p-chlorophenylalanine, PCPA) or chronic (5,7-dihydroxytryptamine, 5,7-DHT) brain 5-HT depletions were studied in rats and compared with the actions of a 5-HT uptake inhibitor (fluoxetine) and 5-HT_1B/2C receptor agonists [1-(3-trifluoromethyl-phenyl)-piperazine and 1-(3-chlorophenyl) piperazine]. The anorexia caused by these agonists was enhanced in rats with 5,7-DHT lesions, possibly a result of receptor supersensitivity. In contrast, fluoxetine anorexia was somewhat reduced in one study and was unchanged in a second. Both dF and dNF anorexias were enhanced in rats with 5,7-DHT lesions. In contrast, the anorectic effects of either dF or dNF were unchanged in PCPA-treated rats relative to controls. Compared with controls, 5,7-DHT-lesion rats showed greatly increased dF- and dNF-induced Fos-like immunoreactivity (ir) in the paraventricular (PVN) and supraoptic (SON) hypothalamic nuclei, and in the median preoptic area (MnPO), but were similar to controls in most other areas. PCPA pretreatment increased dF- and dNF-induced Fos-ir in the PVN, SON, and MnPO. In controls, equianorectic doses of dF and dNF induced Fos-ir in similar brain regions, but dNF produced relatively larger effects than dF in SON, PVN, and MnPO. The data are discussed in terms of multiple pathways in the anorectic actions of dF and dNF.