Recurrent epileptic seizures in the rat enhance the expression of neuropeptide Y (NPY) and its mRNA in various brain areas including the hippocampus, cerebral cortex and the amygdala. In the hippocampus, the most prominent expression of NPY is observed in mossy fibers and in GABAergic interneurons. At the same time, expression of Y2 receptors is also increased whereas Y1 receptors are reduced. Similar changes in Y1 and Y2 receptors were observed in the hippocampus of patients with temporal lobe epilepsy (TLE). In contrast to the rat, NPY expression is not enhanced in mossy fibers in TLE. In the same tissue, surviving NPY interneurons show marked axonal sprouting into areas innervated by mossy fibers (dentate hilus, stratum lucidum, inner molecular layer of the dentate gyrus). Stimulation of presynaptic Y2 receptors inhibits glutamate release, and exert an anticonvulsant action in experimental models. Y1 receptors mediate a weak excitatory component of NPY action. These findings suggest that changes in the NPY system induced by seizures represent an endogenous adaptive mechanism aimed at counteracting hyperexcitability underlying epileptic activity. This concept is strongly supported by evidence that genetically modified rats overexpressing the NPY gene are less susceptible to seizures while deletion of NPY or Y2 receptor genes results in increased susceptibility to seizures.