Distribution and regulation of neuropeptide Y and its receptors in the human and rat brain : role in affective disorders

Abstract: Neuropeptide Y (NPY) is one of the most abundant peptides found within the mammalian brain. Many studies have documented that this 36 amino acid peptide exerts a wide range of central effects. In the CNS, the physiological actions of NPY are thought to be primarily mediated via interactions at six NPY receptor subtypes, Y1-Y6, which have distinct anatomical distribution and pharmacological properties. Based on the limited information known about the anatomical organization of the NPY system in the human central nervous system (CNS), the regional mRNA expression of NPY and its receptors, Y1 and Y2, were analyzed in the post-mortem human brain. The results of these studies demonstrated that there is a differential distribution of Y1 and Y2 mRNA-expressing cells in the human brain, with Y1 prevalent in most neocortical regions as well as in the striatum, while Y2 mRNA expression is most abundant in the hippocampus and the cerebellum. Using double labeling in situ hybridization, Y2, but not Y1 mRNA was found to be colocalized in a subpopulation of NPY mRNA of neurons of the human cerebral cortex, hippocampus, and amygdala suggesting a role for Y2 as pre-junctional autoreceptor with a post- junctional role of both Y1 and Y2 receptors. Quantitative receptor autoradiography confirmed that Y1 receptor binding sites are low in the human brain despite very high Y1 mRNA expression. Post-mortem delay studies in the rat brain demonstrated that there is a differential post-mortem. susceptibility of the two receptors (Y1 more sensitive than Y2) that could partly account for the paucity of Y1 vs. Y2 binding sites found in the human brain. The anatomical relationship between NPY and Y1 receptor was also investigated in the rat brain using double labeling immunohistochemistry with antibodies selective for NPY and Y1. The Y1 immunoreactivity was found in the cytoplasm and in the membrane in discrete populations of neuronal cell bodies and their dendrites. The Y1 immunoreactive cell and dendrites often lack any direct proximity to NPY nerve terminal networks which demonstrates that NPY and Y1 are not colocalized. in the same neuron and that volume transmission may be an important mode of communication in Y1 receptor-mediated NPY transmission. Evident species differences in the anatomical distribution of Y1 and Y2 receptors between the rat and the human brain were observed in a few brain regions, suggesting some caution when extrapolating to humans results obtained in the rat regarding NPY receptors functions in these brain areas. Emerging evidence has suggested the involvement of NPY in depression. To investigate the possible role of the NPY system in affective disorders, a genetic animal model of depression, the Flinder Sensitive Line rats, and post-mortem prefrontal cortical specimens from human subjects diagnosed with affective disorders were studied. NPY and Y1 receptors were found to be altered in specific brain regions of the Flinder Sensitive Line rats as compared to the control Flinder Resistant Line rats, while Y2 receptors were found unchanged, sustaining a role of Y1 but not Y2, receptors in depression. Impaired NPY, but not Y1 mRNA expression was found in subjects affected by bipolar disorder. Overall, these findings give support to the hypothesis of a role of NPY in the pathophysiology of affective disorders, but further studies are needed to clarify the contribution of the Y1 and Y2 receptors in these pathologies.