Differential modulation of NMDA-stimulated [3H]dopamine release from rat striatum by neuropeptide Y and sigma receptor ligands.

Although the identity of the endogenous ligands for sigma (sigma) receptors is unknown, neuropeptide Y (NPY) has been named as a possible candidate for a natural transmitter at these receptors. Using a superfusion system, we compared the effect of NPY on NMDA-stimulated [3H]dopamine release in rat striatum to that of the sigma agonists (+)-pentazocine and BD737. In contrast to (+)-pentazocine- or BD737-mediated inhibition of release, NPY enhanced release. However, the same sigma antagonists (BD1008, DuP734, haloperidol and DTG) that reverse (+)-pentazocine- or BD737-mediated inhibition, as well as a Y receptor antagonist, PYX-1, all reversed the enhancement. PYX-1 also reversed the (+)-pentazocine- and BD737-mediated inhibition of release. Peptide YY (PYY) and [Leu31,Pro34]NPY did not mimic the effect of NPY. NPY13-36 enhanced release to the same extent as NPY but the effect was not reversed by sigma antagonists. Our findings are consistent with the potential role of NPY as an endogenous ligand for a subtype of sigma receptor with characteristics different from Y1, Y2 and Y3 receptors but sensitive to PYX-1.