Vol. 284, Issue 2, 553-560, February 1998

Modulation of [³H]Dopamine Release from Rat Nucleus Accumbens by Neuropeptide Y May Involve a Sigma₁-like Receptor¹

David T. Ault, Julie M. Radeff and Linda L. Werling

Neuroscience Program and Department of Pharmacology, The George Washington University Medical Center, Washington, DC

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 receptors on the basis of its ability to compete for  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  agonist (+)pentazocine inhibited release. However, four  antagonists, one of which is ₁ selective, as well as a Y receptor antagonist, all reversed the enhancement by NPY and the inhibition by (+)pentazocine. A ₂-selective antagonist had no effect on either NPY-mediated enhancement or (+)pentazocine-mediated inhibition. [Leu³¹,Pro³⁴]NPY and NPY_13-36 also enhanced release, but the effects were not reversed by  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  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  receptors, in the regulation of dopamine levels in areas of brain critical to psychosis and reinforcement.