During fasting, corticotropin-releasing hormone (CRH) mRNA decreases in the hypothalamic paraventricular nucleus (PVN), but the mechanism by which this takes place is not well understood. To test the hypothesis that the melanocortin system may be involved in the regulation of CRH mRNA in the PVN during fasting, the effect of intracerebroventricularly administered alpha-melanocyte stimulating hormone (MSH) on CRH mRNA in the PVN was studied in fasted animals by in situ hybridization histochemistry. Whereas fasting suppressed CRH mRNA levels in the PVN, alpha-MSH at doses of 150 and 300 ng every 6 h for 64 h prevented the fasting-induced suppression of CRH gene expression in the PVN. These data indicate that the suppression of alpha-MSH synthesis may be responsible for the decreased CRH gene expression in the PVN during fasting.