Effects of levodopa on striatal monoamines in mice with levodopa-induced hyperactivity

Abstract

The present study examines striatal monoamine changes in a murine model of levodopa-induced dyskinesia (LID), a common side effect of Parkinson's disease (PD) therapy. Mice previously exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and later made hyperactive with high-dose (200mg/kg, i.p.) exogenous levodopa were compared to mice with normal motor behavior who received either levodopa without previous MPTP or no treatment at all. Using high-performance liquid chromatography, dopamine (DA), serotonin (5HT), noradrenaline (NA) and their metabolites were then measured in samples of striatum versus olfactory bulbs as controls. In the olfactory bulb, exogenous levodopa caused increased DA levels and increased DA-, 5HT- and NA-turnover rates, but decreased 5HT and NA levels, regardless of animal activity. These trends were also seen in the striatum, but animals with LID seemed to have unique differences. Thus, in mice sacrificed at the height of their hyperactive LID behavior, striatal DA and 5HT were significantly lower and DA- and 5HT-turnover rates were significantly higher than control animals with normal motor behavior, regardless of levodopa exposure. In addition, the expected increased NA-turnover rate seen in other specimens from animals exposed to levodopa was not seen in the striatum of LID mice. The results of the present study demonstrate that there is a distinct profile of striatal monoamines conducive to LID that must be considered when trying to explain the effects of anti-LID drugs utilizing monoamine receptors.