The distribution of neuropeptide Y (NPY) receptor sites was investigated in certain mammalian species using receptor autoradiography and membrane binding assay techniques. NPY receptor sites are discretely distributed throughout the central nervous systems of hamster, rat, guinea pig and monkey but are particularly concentrated in cortex and hippocampus. NPY receptor autoradiography techniques also revealed important labelling of numerous thalamic nuclei while most hypothalamic nuclei showed surprisingly low densities of NPY receptor sites, considering the high levels of NPY-like immunoreactivity in this brain area. The widespread distribution of NPY receptor sites suggests that this peptidergic system must have important roles in mammalian central nervous system. In particular, the possible involvement of NPY in cognitive function deserves further investigation since we observed that ($ sp3$H) NPY receptor site densities are decreased in temporal cortex and hippocampus of individuals decreased with Alzheimer's disease. / The possible existence of NPY/peptide YY (PYY) receptor subtypes was investigated in the rat brain. Overall, the similar autoradiographic distribution of ($ sp{125}$I) BH-NPY and ($ sp{125}$I) PYY in most areas suggests that these two receptor probes most likely interact with the same population of NPY/PYY receptor sites. ($ sp{125}$I) PYY may recognize both a high and low affinity state/subtype of NPY/PYY receptors while ($ sp{125}$I) BH-NPY recognize a single affinity state of receptor having the binding characteristics of the low affinity ($ sp{125}$I) PYY receptor state/subtype. The exact nature of this high affinity receptor state/subtype remains to be established. / Finally, the structural requirements of NPY receptors in central (CNS) and peripheral (PNS) nervous systems were also examined with a binding assay on rat brain membrane preparation and with the rat vas deferens bioassay preparation. The amino acid residues responsible for the activation of NPY receptors in the rat vas deferens preparation lie in the C-terminal half of the NPY molecule as revealed by the loss of potency, but not of biological activity with C-terminal fragments up to NPY$ sb{18-36}$. The N-terminal portion of the NPY molecule appears to be mostly important to insure adequate affinity for central and peripheral NPY receptors. Moreover, a series of NPY analogs revealed that the two tyrosine residues in position 20 and 21 are not directly involved in NPY receptor activation in this bioassay preparation, although they appear relatively important for the maintenance of adequate affinity for the receptors. Interestingly, modifications of the tyrosine residue in position 20 led to the development of two analogs demonstrating a certain degree of selectivity for the PNS receptors while other modifications of tyrosine residues in position 21 may provide some selectivity for CNS receptor sites. (Abstract shortened by UMI.)
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.74569 |
| Date | January 1990 |
| Creators | Martel, Jean-Claude |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology and Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001167753, proquestno: AAINN66490, Theses scanned by UMI/ProQuest. |
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