When neuropeptide Y (NPY) is administered centrally, meal-anticipatory responses are elicited. If an increase of endogenous NPY is a signal that heralds an imminent large caloric load, timed daily NPY injections may be expected to condition meal-anticipatory responses that facilitate ingestion. Rats received 4-h access to food beginning in the morning and then timed (1600 h), daily third-ventricular injections of NPY or saline for 7 days. On test day (day 8), animals received the conditioning drug (NPY or saline) or the opposite drug. Food was available immediately after injection on test day, and intake was measured. Rats conditioned with NPY and then given saline ate significantly more than rats conditioned with saline and then given saline; they ate the same amount as rats given NPY. Although they ate more, rats trained with NPY did not have changed plasma glucose, insulin, or ghrelin. These data suggest that NPY plays a role in mediating conditionable food-anticipatory responses that help to cope with the effects of large caloric loads.conditioning; learning; food intake SEVERAL LINES OF EVIDENCE suggest that consuming large caloric loads poses a metabolic challenge (36, 39). During and after large meals, glucose, fatty acids, and other nutrients flood into the blood from the gut and consequently perturb the rigorously controlled levels of blood nutrients, and insulin and other hormones must be secreted to reduce and hence tolerate the increments. In an endocrine sense, the postprandial elevation of plasma fuels has been considered a stressor in that plasma catecholamines, adrenocorticotropic hormone, glucocorticoids, and -endorphin are all elevated at that time (10,21,25,36). Although one could argue that individual meal-induced increases in these stress hormones are not major, when hundreds or thousands of meals are considered on a chronic basis, such increases have been implicated in the development of obesity, hypertension, and atherosclerosis (5,18,20,36).Consistent with this view of meals, animals engage in specific behaviors that help minimize the acute metabolic impact of food. In particular, animals adapt by learning to make anticipatory responses that minimize a meal's impact, and, if they are unable to reliably anticipate a meal, they eat smaller meals (24). The premeal secretion of insulin is an adaptive response that minimizes prandial increases of blood glucose (3,35,36), and it is coincident with a premeal reduction in metabolic rate, a premeal elevation of plasma corticosterone, and a premeal increase in body temperature (11,14,23,25), all of which are initiated well in advance of an anticipated meal. The term "cephalic" describes these anticipatory responses because they are initiated by cues in an individual's environment that reliably predict meals, cues that can be considered as conditioned stimuli in a learning sense. As an example, animals readily learn to use time of day to entrain their pattern of food intake. Hence, when maintained on a stable light-dark schedule, they consume the l...