CHRONIC LEVODOPA IS NOT TOXIC FOR REMAINING DOPAMINE NEURONS, BUT INSTEAD PROMOTES THEIR RECOVERY, IN RATS WITH MODERATE NIGROSTRIATAL LESIONS

Orally administered levodopa remains the most effective symptomatic tr eatment for Parkinson's disease (PD). The introduction of levodopa the rapy is often delayed, however, because of the fear that it might be t oxic for the remaining dopaminergic neurons and, thus, accelerate the deterioration of patients. However, in vivo evidence of levodopa toxic ity is scarce. We have evaluated the effects of a 6-month oral levodop a treatment on several dopaminergic markers, in rats with moderate or severe 6-hydroxydopamine-induced lesions of mesencephalic dopamine neu rons and sham-lesioned animals. Counts of tyrosine hydroxylase (TH)-im munoreactive neurons in the substantia nigra and ventral tegmental are a showed no significant difference between levodopa-treated and vehicl e-treated rats. In addition, for rats of the sham-lesioned and severel y lesioned groups, immunoradiolabeling for TH, the dopamine transporte r (DAT), and the vesicular monoamine transporter (VMAT2) at the striat al level was not significantly different between rats treated with lev odopa or vehicle. It was unexpected that quantification of immunoautor adiograms showed a partial recovery of all three dopaminergic markers (TH, DAT, and VMAT2) in the denervated territories of the striatum of moderately lesioned rats receiving levodopa Furthermore, the density o f TH-positive fibers observed in moderately lesioned rats was higher i n those treated chronically with levodopa than in those receiving vehi cle. Last, that chronic levodopa administration reversed the up-regula tion of D2 dopamine receptors seen in severely lesioned rats provided evidence that levodopa reached a biologically active concentration at the basal ganglia. Our results demonstrate that a pharmacologically ef fective 6-month oral levodopa treatment is not toxic for remaining dop amine neurons in a rat model of PD but instead promotes the recovery o f striatal innervation in rats with partial lesions.