Y1-receptors regulate the expression of Y2-receptors in distinct mouse forebrain areas

Y-receptor-knockout mice have become an important tool to elucidate specific physiological roles of individual Y-receptors. However, their phenotypes are not always confirmatory to results obtained by pharmacological investigations in vivo or in vitro. These discrepancies may, at least in part, be due to compensatory changes in the expression of remaining Y-receptor types. To determine whether deletion of individual Y-receptors results in altered mRNA expression and/or binding toward other Y-receptor types, we applied in-situ hybridization and radioligand-binding studies on brain slices of Npy1r-, Npy2r- or Npy5r-knockout mice. Significant changes were seen in Y1-receptor-deficient mice. Thus, Y2-receptor mRNA and (125)I-peptide YY(3-36) binding in the hippocampus proper were increased by up to 55% and 89%, respectively. Similar increases in (125)I-peptide YY(3-36) binding were observed in the caudo-dorsal extension of the lateral septum, an area heavily targeted by hippocampal projections and involved in Y1-receptor-regulated anxiety. Increased (125)I-peptide YY(3-36) binding and Y2-receptor mRNA levels were also observed in the medial amygdaloid nucleus. In contrast, (125)I-peptide YY(3-36) binding was reduced in the central amygdaloid nucleus. Y2-receptor mRNA in the intermediate part of the lateral septum was reduced by 42%. Only minimal changes were observed in Y2- or Y5-receptor-deficient mice. Our results demonstrate that compensatory changes in the expression of Y2-receptors occur in Y1-receptor-deficient mice. These adaptations are likely to contribute to changed physiological function. Thus, alterations in Y2-receptors have to be taken in account upon discussion of Y1-receptor function, especially in emotional aspects like anxiety and aggression, but also alcoholism.