| Neuropeptide Y (NPY) has been shown to interact with dopamine (DA) systems and may play a role in DA-related psychotic disorders. Because of this association, we determined and compared the effects of psychomimetic drugs on NPY systems in the basal ganglia. We observed that phencyclidine, methamphetamine (METH), (+)methylenedioxymethamphetamine, and cocaine similarly reduced the striatal content of NPY-like immunoreactivity (NPYLI) from 54%–74%. METH decreased NPYLI in specific regions of striatum and nucleus accumbens at time points prior to one week after exposure, but at 1 week NPYLI had returned to control levels. There was no effect of METH on NPYLI in the substantia nigra or globus pallidus. The DA D-1 receptor antagonist SCH-23390, but not the DA D-2 receptor antagonist eticlopride, blocked the effects of METH on NPYLI. We also examined the effects of METH treatment on preproNPY mRNA levels in striatum There was no change in the amount of expression of preproNPY mRNA per cell, but there was a significant increase in the number of neurons expressing preproNPY mRNA 3–15 hr after exposure to METH. Values returned to normal by 1 week after exposure. The D-1 DA receptor antagonist SCH-23390, but not the D-2 DA receptor antagonist eticlopride, again blocked the effect. These results indicate that the METH-induced changes in NPY in the striatum are mediated by D-1 DA receptors. Because we saw decreased levels of striatal NPYLI, but increases in the number of cells expressing preproNPY, and no evidence for toxicity, we conclude that the most likely explanation for the decreased NPYLI, levels is increased release of NPY from the striatal interneurons. Because NPY has been shown to decrease the release of DA in the striatum the increased release is most likely an attempt of the NPY interneurons to reduce the release of DA from nigrostriatal neurons. Depletion of NPY stores, as reflected by decreased tissue levels of NPYLI, may lead to a nigrostriatal neurons. Depletion of NPY stores, as reflected by decreased tissue levels of NPYLI, may lead to a subsequent inability of NPY neurons to regulate subcortical DA release, leading to DA-induced psychosis. |
