Effects of stimulants of abuse on extrapyramidal and limbic neuropeptide Y systems.

Neuropeptide Y (NPY), an apparent neuromodulating neuropeptide, has been linked to dopamine systems and dopamine-related psychotic disorders. Because of this association, we determined and compared the effects of psychotomimetic drugs on extrapyramidal and limbic NPY systems. We observed that phencyclidine, methamphetamine (METH), (+)methylenedioxymethamphetamine (MDMA), and cocaine, but not (-)MDMA, similarly reduced the striatal content of NPY-like immunoreactivity from 54% (phencyclidine) to 74% [(+) MDMA] of control. The effects of METH on NPY levels in the nucleus accumbens, caudate nucleus, globus pallidus, and substantia nigra were characterized in greater detail. We observed that METH decreased NPY levels in specific regions of the nucleus accumbens and the caudate, but had no effect on NPY in the globus pallidus or the substantia nigra. The dopamine D1 receptor antagonist SCH-23390 blocked these effects of METH, suggesting that NPY levels throughout the nucleus accumbens and the caudate are regulated through D1 pathways. The D2 receptor antagonist eticlopride did not appear to alter the METH effect, but this was difficult to determine because eticlopride decreased NPY levels by itself. A single dose of METH was sufficient to lower NPY levels, in some, but not all, regions examined. The effects on NPY levels after multiple METH administrations were substantially greater and persisted up to 48 h after treatment; this suggests that synthesis of this neuropeptide may be suppressed even after the drug is gone. These findings suggest that NPY systems may contribute to the D1 receptor-mediated effects of the psychostimulants.