Receptors for neuropeptide Y (NPY) are widely distributed throughout the mammalian brain. Using indirect labeling methods, the human brain was reported to contain predominantly the Y 2 receptor subtype, whereas the rat brain contains a mixture of Y 1 and Y 2 receptor subtypes. To more accurately assess NPY receptors in the human brain, we used the Y 1 - and Y 2 -selective radioligands [ 1 2 5 I][Leu 3 1 ,Pro 3 4 ]PYY and [ 1 2 5 I]PYY(3-36), respectively, to examine NPY receptors in the human frontal cortex. Contrary to an earlier report, abundant Y 1 binding sites were found in homogenates of human frontal cortex. Moreover, saturation analysis showed similar densities of both Y 1 (K d = 433 ± 36 pM, Bmax = 313 ± 15 fmol/mg protein) and Y 2 (K d = 444 ± 39 pM,B max = 458 ± 22 fmol/mg protein) receptor subtypes in the human frontal cortex. Subsequently, Northern blot analysis revealed abundant expression of Y 1 mRNA, with very low levels of Y 2 mRNA, in cerebral cortex and in other areas of the human brain. These findings were confirmed by competitive RT-PCR in the human frontal cortex. Therefore, it appears that Y 1 binding sites and mRNA are expressed abundantly in the human frontal cortex and, unlike earlier findings, suggest that the human brain contains a mixture of Y 1 and Y 2 receptor subtypes.