Food deprivation after treatment blocks the multiple-day hyperphagic response to SHU9119 administration

The multiple-day hyperphagic effect of the melanocortin 3/4 receptor antagonist, SHU9119, is apparently abolished when rats are food-deprived for 24 h after central (4th-ventricular) injection. Here, we affirmed this indication, and addressed the possibility that the orexigenic potency of SHU9119 is simply masked by the refeeding hyperphagia that follows food deprivation. This explanation is discounted by our finding that the drug response in ad libitum-fed rats and the deprivation response are expressed at different, and non-overlapping, times of day. We then asked whether food consumption during a hypothesized critical period in the hours after treatment is necessary for expression of the hyperphagic response to SHU9119, or alternatively, whether blood-borne signals that emerge only after an extended period of food restriction underlie the drug-state interaction. Evidence favoring the latter interpretation was derived from a series of four experiments over which the timing and duration of food access after drug administration was varied. The results indicate an interaction between melanocortin receptor activity and the metabolic state of the animal, and constrain our thinking about the peripheral signals and central mechanisms that underlie this interaction.