The respective distribution of neuropeptide Y Y 1 , Y 2 , Y 4 , and Y 5 receptor subtypes was investigated in rodents (rat and mouse), guinea pig, and primates (marmoset and vervet monkeys and human) brains, representing three orders of mammals. [ 125 I][Leu 31 ,Pro 34 ]PYY (total Y 1 -like; Y 1 , Y 4 , and Y 5 ) and [ 125 I]PYY 3-36 (total Y 2 -like; Y 2 and possibly Y 5 ) binding sites were discretely but similarly distributed in the rat and mouse brain, each having its unique pattern. In contrast, surprisingly low levels of [ 125 I]PYY 3-36 binding sites were found in the guinea pig brain including in the hippocampal formation. [ 125 I][Leu 31 ,Pro 34 ]PYY/BIBP3226insensitive binding sites (Y 5 -like) were found in different areas of the rat and guinea pig brains. The primate brains also revealed a different distribution binding profile for these various NPY receptor subtypes. Although the human and vervet brains contained very low amounts of [ 125 I][Leu 31 ,Pro 34 ]PYY sites (Y 1 -like) in most brain regions, except for the dentate gyrus of the hippocampus, the marmoset brain contains significant amounts of both [ 125 I][Leu 31 ,Pro 34 ]PYY (Y 1 -like) and [ 125 I]PYY 3-36 (Y 2 -like) binding sites. Additionally, [ 125 I][Leu 31 ,Pro 34 ]PYY/BIBP3226-insensitive binding sites were not clearly detected in the vervet and human brains. On the other hand, Y 5 -like binding sites were observed in few regions of the marmoset brain. Finally, [ 125 I]hPP (Y 4 /Y 5 -like) were very discretely distributed in the rat brain, being concentrated in the paraventricular nucleus of the hypothalamus and the interpeduncular nucleus. The marmoset brain is apparently not enriched with specific [ 125 I]hPP sites. Taken together, these data show that significant species differences exist in the level of expression and distribution of various NPY receptor subtypes in the mammalian brain.