title: Lack of effects by sigma ligands on neuropeptide Y-induced G-protein activation in rat hippocampus and cerebellum.
abstract: It has been suggested that neuropeptide Y (NPY) and sigma (sigma) receptor ligands may share a putative NPY/sigma receptor in rat brain. To study whether NPY and sigma receptor ligands have an inverse agonism at this putative NPY/sigma receptor, we measured their effects on G-protein activity in rat brain. Using [35S]GTPgammaS autoradiography, we found that NPY-induced G-protein activation exhibited a discrete distribution pattern in rat brain. G-protein activation in superficial cortical layers and hippocampal CA1-3 region was mainly attributed to Y1 and Y2 receptors, respectively. In the presence of 10 microM sigma-receptor agonist BD737 or 10 microM sigma-receptor antagonist haloperidol, the distribution and density of [35S]GTPgammaS binding stimulated by 10 nM NPY was not significantly altered. In rat cerebellar membranes, NPY stimulated high-affinity GTPase activity in a dose-related manner, with maximal effects of 29% increase over basal level seen at 500 nM. This NPY-elicited GTPase activity was not significantly affected by micromolar concentrations of the sigma-receptor antagonists Dup734 or haloperidol. Since no significant effects by sigma-receptor ligands on NPY-induced G-protein activation were observed, we did not see an inverse agonism of NPY and sigma-receptor ligands at the putative NPY/sigma receptor measured at the level of G-protein activation, suggesting that sigma receptors and NPY receptors do not represent a common population in rat hippocampus and cerebellum. It is also suggested that G-protein activation is not a convergent point for the signal transduction mechanisms of NPY receptors and sigma receptors.
authors.affiliation: Neuroscience Program, The George Washington University Medical Center, Washington, DC 20037, USA.
authors.forename: W
authors.initials: W
authors.lastname: Hong
authors.forename: L
authors.initials: L
authors.lastname: Werling
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D003514:Cyclohexylamines / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008024:Ligands; D008297:Male; D009478:Neuropeptide Y / Q000378:metabolism / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000187:drug effects* / Q000378:metabolism; D017480:Receptors, sigma / Q000187:drug effects* / Q000378:metabolism; D013347:Subcellular Fractions; D013462:Sulfur Radioisotopes
chemical_list: D000700:Analgesics; D003514:Cyclohexylamines; D018492:Dopamine Antagonists; D008024:Ligands; D009478:Neuropeptide Y; D011759:Pyrrolidines; D017476:Receptors, Neuropeptide Y; D017480:Receptors, sigma; D013462:Sulfur Radioisotopes; C075567:BD 737; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D006220:Haloperidol