Expression and characterization of the neuropeptide Y Y5 receptor subtype in the rat brain

The neuropeptide Y Y5 receptor subtype has generated great interest, especially regarding its possible involvement in feeding behaviors. However, its distribution and sites of expression in the mammalian brain are, in large part, unknown because of the lack of selective tools. We demonstrate in this study that specific [125I][Leu31, Pro34]PYY binding is competed in a biphasic manner by BIBP3226, a Y1 receptor antagonist, demonstrating the existence of sensitive and insensitive sites to BIBP3226. Assays performed by using [125I][Leu31,Pro34]PYY in the presence of 1 microM BIBP3226 to block the Y1 receptor subtype revealed a pharmacological profile highly similar to the cloned Y5 receptor. Moreover, results obtained with GW1229 suggest that the Y4 subtype represents only a very small proportion of the total population of NPY receptors in the rat brain. Quantitative receptor autoradiographic data revealed the discrete distribution of [125I][Leu31,Pro34]PYY/BIBP3226-insensitive Y5 sites in the rat brain, with the external plexiform layer of the olfactory bulb, the lateral septum, the anteroventral thalamic nucleus, the CA3 subfield of the ventral hippocampus, the nucleus tractus solitarius, and the area postrema being most enriched. Rather surprisingly, in the hypothalamus, a key structure modulating food intake, only low densities of Y5 binding sites were detected as well as in most other regions of the rat brain. These data suggest that the Y5 receptor protein is expressed and translated by a small percentage of hypothalamic neurons and that the effect of NPY on feeding behaviors likely is mediated by more than one class of NPY receptors. It also indicates that the Y5 receptor may be involved in other biological actions induced by NPY. Taken together, these data represent the first pharmacological demonstration of the expression and discrete localization of the Y5 receptor protein in the rat brain.