Dopamine acts in the striatum principally through the D1 and D2 dopamine receptor subtypes, which are segregated to the direct and indirect striatal projection neurons, respectively. As a consequence, degeneration of the dopamine input to the striatum results in opposing affects in these pathways. The resulting functional imbalance is thought to be responsible for the bradykinesia of Parkinson’s disease, which may be temporarily normalized by dopamine replacement therapy. However, direct striatal projection neurons become irreversibly supersensitive to D1 dopamine receptor activation, despite the fact that there is an actual decrease in receptor number. Recent studies show that this D1-supersensitive response results from a switch from the normal D1-mediated activation of protein-kinase A to an aberrant activation of ERK1/2/MAPkinase. This switch in D1-receptor-mediated regulation of protein kinase systems responsible for neuronal plasticity is suggested to underlie dyskinesia produced by L-DOPA treatment of Parkinson’s disease.
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