We have previously shown that central administration of prolactin-releasing peptide (PrRP) inhibits food intake and body weight gain in rats (Lawrence et al. 2000), and have suggested that PrRP, acting through its putative receptor GPR10, may play a role in mediating the central anorexigenic effects of cholecystokinin (CCK) (Lawrence et al. 2002). Here we examine the effects of CCK and PrRP on feeding in mice, including animals in which the PrRP-receptor gene has been disrupted (GPR10-/-). Intracerebralventricular (i.c.v.) administration of PrRP (1-4 nmol, in 1μl) to wild type C57B6/J mice, was found to inhibit feeding in a dose-dependent manner under both fasted and ad libitum-fed conditions. Over the first hour of feeding, PrRP (2nmol) reduced feeding in pre-fasted mice by approximately 40% (vehicle: 0.53 ± 0.05g, PrRP: 0.32 ± 0.05g; P < 0.05) and over 50% in ad libitum-fed mice (vehicle: 0.26 ± 0.03g, PrRP: 0.12 ± 0.01g; P < 0.05). Food intake was inhibited to a similar degree following intraperitoneal (i.p.) administration of CCK (8μg/kg). Furthermore, as shown previously in the rat, immunohistochemical detection of c-fos protein synthesis, a common marker of neuronal activation, revealed some overlap in the brain regions activated by icv administration of PrRP and i.p. administration of CCK. GPR10-/- mice demonstrate adult-onset obesity, exhibiting a significantly higher mean body weight at 18 weeks of age (GPR10-/-: 41.3 ± 1.6g; GPR10+/+: 34.6 ± 1.0g; P < 0.01), and significantly higher epididymal fat pad mass (GPR10-/-: 1.3 ± 0.2g; GPR10+/+: 0.6 ± 0.1g; P < 0.01). In contrast to the observations made in wild type mice, neither PrRP (2nmol, i.c.v.) nor CCK (15μg/kg, i.p.) inhibited food intake in GPR10-/- mice. These findings suggest that PrRP is involved in regulating the balance between food intake and energy expenditure, and may be a key intermediary in the central satiating actions of CCK. All animals were humanely killed at the termination of chronic experiments.