Effects of chronic fenfluramine administration on hypothalamic neuropeptide mRNA expression

Appetite suppressants lose efficacy when given chronically; the mechanisms are unknown. We gave male rats once-daily dl-fenfluramine (dl-FEN, 5 mg/kg, i.p.) injections for 15 days and measured mRNA expression of corticotropin releasing factor (CRF), neuropeptide Y (NPY) and proopiomelanocortin (POMC) in hypothalamic neurons on days 1, 2 and 15. dl-FEN decreased food intake on days 1-2 but not on day 15. The drug increased CRF mRNA and decreased NPY mRNA on days 1-2; on day 15, NPY mRNA was normal, but CRF mRNA remained elevated. No changes occurred in POMC mRNA. Thus, only the NPY mRNA response to dl-FEN correlated with changes in food intake over time in a manner consistent with the known effects of NPY on food intake.