Modulation of [3H]Dopamine release from rat nucleus accumbens by neuropeptide Y may involve a sigma1-like receptor

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 sigma receptors on the basis of its ability to compete for sigma 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 sigma agonist (+)pentazocine inhibited release. However, four sigma antagonists, one of which is sigma1 selective, as well as a Y receptor antagonist, all reversed the enhancement by NPY and the inhibition by (+)pentazocine. A sigma2-selective antagonist had no effect on either NPY-mediated enhancement or (+)pentazocine-mediated inhibition. [Leu31,Pro34]NPY and NPY13-36 also enhanced release, but the effects were not reversed by sigma 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 sigma 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 sigma receptors, in the regulation of dopamine levels in areas of brain critical to psychosis and reinforcement.