Abstract

Sigma receptors are located in limbic areas, including the nucleus accumbens, where increased dopamine levels have been linked to psychosis and reinforcement. Neuropeptide Y (NPY) has been named as a possible endogenous ligand for a subpopulation of ς receptors on the basis of its ability to compete for ς receptor binding. Using a superfusion system, we found that NPY enhanced N-methyl-d-asparate-stimulated [³H]dopamine release in rat nucleus accumbens, whereas the prototypical ς agonist (+)pentazocine inhibited release. However, four ς antagonists, one of which is ς₁ selective, as well as a Y receptor antagonist, all reversed the enhancement by NPY and the inhibition by (+)pentazocine. A ς₂-selective antagonist had no effect on either NPY-mediated enhancement or (+)pentazocine-mediated inhibition. [Leu³¹,Pro³⁴]NPY and NPY_13–36also enhanced release, but the effects were not reversed by ς antagonists. Peptide YY did not mimic the effect of NPY. Our findings are consistent with the potential role of NPY as an endogenous ligand for a subtype of ς receptor with characteristics different from Y₁, Y₂ and Y₃ receptors but sensitive to Ac-[3-(2,6-dichlorobenzyl)Tyr²⁷,d-Thr³²NPY-(27–36)amide. Our findings suggest a role for NPY, via ς receptors, in the regulation of dopamine levels in areas of brain critical to psychosis and reinforcement.