Three common dosing regimens of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced
model of Parkinson's disease (PD) were compared in C57BL/6 mice on behavior, striatal
and extra-striatal neurotransmission, and brain cytokines, to clarify the differences
between regimens on these variables. Acute regimen: Rotorod performance and open field
grooming were decreased. Striatal dopamine (DA) was depleted, but DA turnover increased.
Striatal noradrenalin (NA), frontal cortex serotonin (5-HT) and midbrain NA and DA
were all depleted. Sub-acute regimen: Opposite to the acute regimen, rotorod and pole
test performance, and open field grooming were all increased. Striatal DA was depleted,
but DA turnover was increased more than in the acute regimen. Striatal 5-HT turnover
and cortical NA were increased as well. Chronic regimen: Rotorod performance was impaired,
but open field distance moved increased. Striatal DA was severely depleted and DA
and 5-HT turnover strongly increased. Striatal 5-HT, frontal cortex NA and DA, and
cortical DA were all depleted. Pro-inflammatory cytokines interleukin (IL)-1beta,
tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, granulocyte macrophage-colony
stimulating factor (GM-CSF) and IL-10 were only increased in the chronic regimen,
but these cytokines were found to be similarly related to striatal DA turnover in
all regimens. The study demonstrated that the presence of behavioral differences between
regimens may depend on the type of behavioral tests used and the extent to which dopaminergic,
non-dopaminergic and extra-striatal neurotransmission are affected in the regimens.
The study also provided additional evidence for the validity of the relatively new
chronic MPTP/probenecid model. In all, the results suggested that dosing regimens
should be carefully pre-considered.