Activity-based anorexia (ABA) mimics starvation and hyperactivity of anorexia nervosa patients in rats. Activation of the melanocortin (MC) system leads to hypophagia and increased energy expenditure in ad libitum fed rats. Therefore, activation of the MC system might underlie the development and propagation of ABA. Pro-opiomelanocortin (POMC) gene expression is normally decreased during negative energy balance. Strikingly, we found a transient up-regulation of POMC mRNA levels in the arcuate nucleus during the development of ABA, indicating a hyperactive MC system. However, wheel running and food intake were not influenced by treating ABA rats with the competitive antagonist SHU9119. This suggests that agonism of MC receptors by endogenous α-melanocyte-stimulating hormone (α-MSH) levels does not underlie ABA. Instead, treatment with the inverse agonist AgRP(83—132) did ameliorate signs of ABA. This implies that modulation of constitutive MC receptor activity rather than antagonizing putative α-MSH release contributes to the development and propagation of ABA.