CHARACTERIZATION OF NEUROPEPTIDE-Y RECEPTOR SUBTYPES IN THE NORMAL HUMAN BRAIN, INCLUDING THE HYPOTHALAMUS

The aim of the present study was to investigate the existence and dist ribution of neuropeptide Y receptor subtypes in various regions of the normal human brain using the peptide YY derivative receptor probes, [ I-125][Leu(31),Pro(34)]polypeptide YY/I-1 and [I-125]polypeptide YY3-3 6/Y-2, in addition to the non-selective ligand [I-125]polypeptide YY. Membrane binding assays performed with post mortem frontal cortex homo genates revealed that [I-125]polypeptide YY and [I-125]polypeptide YY3 -36 bound in a time- and protein concentration-dependent manner. Very low amounts of specific [I-125][Leu(31),Pro(34)]polypeptide YY binding could be detected even in the presence of high amounts of protein, co ntrasting with results obtained with [I-125]polypeptide YY and [I-125] polypeptide YY3-36, a preferential YY receptor probe. Analysis of satu ration isotherms revealed that [I-125]polypeptide YY3-36 bound to a si ngle class of high-affinity sites (0.5-2 nM). Significantly higher bin ding capacities were evident for [I-125]polypeptide YY3-36 as compared to [I-125][Leu(31),Pro(34)]polypeptide YY, suggesting that the human frontal cortex, in contrast to the rat, is mostly enriched with Y-2 re ceptors. Ligand selectivity profile confirmed the hypothesis that poly peptide YY3-36 neuropeptide Y and polypeptide YY but nor the [Leu(31), Pro(34)] derivatives are potent competitors of [I-125]polypeptide YY a nd [I-125]polypeptide YY3-36 binding sites. Autoradiographic studies d emonstrated further that cortical areas, as well as most other regions of the human brain, are particularly enriched with Y-2/[I-125]polypep tide YY3-36 sites, while only low to very low amounts of Y-1 binding w ere detected except in the dentate gyrus of the hippocampal formation. In the human hypothalamus, a preponderance of Y-2 binding sites was a lso noted. Taken together, these results clearly establish that the di stribution of the Y-1 and Y-2 receptor subtypes in human is different from the rodent brain, the Y-2 subtype being most abundant in the huma n brain. (C) 1997 IBRO.