We have previously demonstrated that neonatal intracerebroventricular (ICV) delivery of neuropeptide Y (NPY), an orexigenic peptide, leads to an immediate increase in body weight gain (24%) with an adult onset decline in food intake(20.8%) and body weight gain (14%) in the female (Varma et al Ped Res 41:1441, 1997). To determine the mechanisms(s) behind these adult onset changes, we delivered 1 μg of NPY (n=19) or 2.5 μl of vehicle (n=20) ICV daily in 2 to 8d rats. At 120d in the females, we assessed the endogenous NPY level in the NPY (n=3) and vehicle (n=3) groups by semi-quantitation of paraventricular NPY immunoreactivity. We also examined the biological effect of NPY in the neonatal NPY (n=6) and vehicle (n=6) groups by directly instilling a repeat dose of NPY (10μg) [neonatal NPY-adult NPY; n=3 or vehicle-NPY; n=3] or vehicle [NPY-vehicle; n=3 or vehicle-vehicle; n=3] at 120d into the paraventricular nucleus by stereotaxic coordinates. Food intake and body weight gain was assessed over 72h after the treatment. A 59% decline in the paraventricular nuclear NPY immunoreactivity was noted in the 120d NPY group(666±93 arbitrary units; p<0.05) when compared to the vehicle group(1642±115). NPY-NPY treatment rescued (+4.6±2g) the decline in body weight observed in the 120d female NPY-vehicle group (-13±4g; p< 0.05), when compared to the body weight at the time of reinjection. This increase was similar to that of the control vehicle-vehicle group(-6.75±2g). Food intake increased (≈ 50%) in tandem with the change in body weight [NPY-NPY=62±5g vs NPY-vehicle=31±5g; p<0.05]. The vehicle-NPY group demonstrated maximal weight gain (+9±1g).We conclude that daily neonatal NPY administration causes an adult-onset body weight loss in the female due to a long term persistence of a decline in endogenous NPY levels with no significant change in its biological effect at the dose administered.