SH-SY5Y cells as a model for sigma receptor regulation of potassium-stimulated dopamine release.

Previous studies in our laboratory using rat brain tissue have shown that neuropeptide Y (NPY) can enhance NMDA- and potassium-stimulated dopamine release from various brain regions and that this enhancement is reversed by sigma (sigma) receptor antagonists. In the current study, we sought to determine whether SH-SY5Y cells are suitable for investigating sigma receptor effects and whether any sigma receptors present are of the subtype responsive to NPY. We compare mechanisms by which the prototypical sigma receptor agonist (+)-pentazocine, and the proposed endogenous sigma receptor ligand NPY regulate potassium-stimulated [(3)H]dopamine release from SH-SY5Y cells. Both (+)-pentazocine and NPY inhibit potassium-stimulated [(3)H]dopamine release. Unlike our studies in rat brain tissue, the effect of NPY on [(3)H]dopamine release is not reversed by sigma receptor antagonists. SH-SY5Y cells appear to be an appropriate model to study the regulation of dopamine release by sigma receptors or by NPY receptors, but this population is not identical to that population identified in brain slices.

Phencyclidine and dizocilpine modulate dopamine release from rat nucleus accumbens via sigma receptors.

Phencyclidine (PCP) binds to many sites in brain, including PCP receptors located within the N-methyl-D-aspartate (NMDA) receptor-operated cation channel and sigma (sigma) receptors. In this study, we compare mechanisms by which PCP, dizocilpine (MK-801), the prototypical sigma receptor agonist (+)-pentazocine, and the proposed endogenous sigma receptor ligand neuropeptide Y regulate potassium (K(+))-stimulated [3H]dopamine release from slices of rat nucleus accumbens. (+)-Pentazocine inhibits K(+)-stimulated [3H]dopamine release, and neuropeptide Y enhances it. Both effects are blocked by sigma(1) and neuropeptide Y receptor antagonists, suggesting possible inverse agonism at a subpopulation of sigma/neuropeptide Y receptors. In contrast, PCP and MK-801 both enhance K(+)-stimulated [3H]dopamine release via sigma(1) and sigma(2) receptor subtypes, as demonstrated by antagonist sensitivity. Regulation of release by both (+)-pentazocine and neuropeptide Y persists in the presence of tetrodotoxin suggests that the sigma/neuropeptide Y receptors mediating the modulation are located presynaptically on dopaminergic nerve terminals, but tetrodotoxin eliminates regulation by PCP and MK-801, suggesting that receptors mediating their effects are located upstream from dopaminergic nerve terminals.

Neuropeptide Y-mediated enhancement of NMDA-stimulated [3H]dopamine release from rat prefrontal cortex is reversed by sigma1 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 [3H]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 sigma1 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 (PYY), [Leu31,Pro34]NPY and NPY(13-36) 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 Y1, Y2 and Y3 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.

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.

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.