Lack of effects by sigma ligands on neuropeptide Y-induced G-protein activation in rat hippocampus and cerebellum

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.