The mechanisms through which leptin, the protein product of the ob gene, affects food intake remain to be determined. To assess whether the actions of leptin depend on modulation of within-meal satiety signals, we measured the effect of third ventricular leptin administration on the satiety actions of CCK. Leptin (10 micrograms) administered 1 h before 30-min access to a liquid diet had no effect on intake when administered alone, but doses of 3.5 or 10 micrograms dose dependently increased the suppression of intake produced by 1 nmol/kg CCK. Examination of patterns of c-Fos activation induced by 3.5 micrograms leptin and 1 nmol/kg CCK revealed that the combination produced significant c-Fos activation within the area postrema and the caudal and medial nucleus of the solitary tract (NST) compared with either leptin or CCK treatments alone. The leptin-CCK combination also resulted in increased c-Fos activation within the paraventricular nucleus of the hypothalamus above that produced by leptin alone. These data suggest that the actions of leptin in food intake are mediated through its ability to modulate responsivity to within-meal satiety signals.