Neuropeptide Y mediated enhancement of NMDA-stimulated [3H]dopamine release from rat prefrontal cortex is reversed by σ1 receptor antagonists

Sigma (sigma) receptors are located in limbic areas, including the prefrontal cortex, where decreased dopamine levels have been linked to negative symptoms. Although the endogenous ligands for sigma receptors are unknown, neuropeptide Y (NPY) has been named as the potential endogenous agonist at these receptors. NPY enhanced NMDA-stimulated [H-3]dopamine release in rat prefrontal cortex. This was in contrast to the inhibition produced by the sigma agonists (+)pentazocine and BD737. However, four sigma antagonists, including one which is sigma(1) selective, that reverse (+)pentazocine-or BD737-mediated inhibition all reversed the NPY-mediated enhancement. In addition, PYX-1, a Y receptor antagonist, reversed both the (+)pentazocine-and BD737-mediated inhibition and the NPY-mediated enhancement of release. Peptide YY (PW), [Leu(31),Pro(34)]Npy and NPY13-36 did not mimic the effect of NPY. Our findings are consistent with NPY acting as an endogenous ligand for a subtype of sigma receptor with characteristics different from Y-1, Y-2 and Y-3 receptors but sensitive to PYX-1. These findings suggest a role for NPY, via sigma receptors, as a modulator of dopamine levels in the prefrontal cortex. (C) 1998 Elsevier Science B.V. All rights reserved.