THE INFLUENCE OF INTERMITTENT L-DOPA TREATMENT ON STRIATAL MOLECULAR MARKERS IN HEMIPARKINSONIAN RATS

Motor complications after chronic l-DOPA treatment in patients with Parkinson's disease may be caused by the fluctuations of l-DOPA availability in the brain that provokes the sensitization of striatal output neurons of dopamine-depleted striatum. The aim of this study was to analyze the effects of intermittent l-DOPA/carbidopa treatment schedule (injection of l-DOPA/carbidopa every fourth day, 6-treatments) on the development of locomotor sensitization of hemiparkinsonian rats to l-DOPA, and on the development of dopaminergic sensitization of striatal output neurons of the indirect and direct pathways. The development of locomotor sensitization was verified by the increased intensity of contralateral turning behavior after the last l-DOPA injection. It is well known that PPT mRNA is expressed predominantly by the neurons of the direct pathway, PENK mRNA by the neurons of the indirect pathway, while GAD67 mRNA is expressed in the neurons of both pathways. Dopaminergic sensitization of striatal output neurons of dopamine-depleted striatum was thus assessed by the analysis of changes of striatal preprotachykinin (PPT), proenkephalin (PENK) and GAD 67 mRNA levels 4 and 12 hours after the last l-DOPA injection. We found, that chronic dopamine depletion by itself down-regulates the expression of striatal PPT mRNA and up-regulates GAD67 and PENK mRNAs. These changes of basal expression were not reversed by the intermittent l-DOPA/carbidopa treatment. However, in dopamine-depleted striatum, the intermittent treatment with l-DOPA induced increased responsiveness of striatal PPT and GAD67, but not PENK mRNA expression, to l-DOPA. Our results are in agreement with the hypothesis, that intermittent l-DOPA treatment induces locomotor sensitization that may be linked to the increased dopaminergic responsiveness of striatonigral neurons of the direct pathway, within dopamine-depleted striatum.