Striatal gene expression involved in adaptive responses to levodopa in parkinsonian models: Relevance to long-term clinical effects of levodopa therapy

Parkinson’s disease is characterized by a loss of dopamine neurons comprising the nigrostriatal pathway. Replacement therapy with the dopamine precursor, levodopa, initially provides symptomatic relief to most patients. Over time, however, an increasing proportion are disabled by motor response complications such as variations in the therapeutic response (“on-off” fluctuations) and abnormal movements that typically occur during the maximal effect of levodopa (peak dose dyskinesias). Clinical studies suggest that a progressive loss of dopamine neurons and secondary postsynaptic changes contribute to the development of these problems. Consistent with the latter proposal, acute levodopa administration to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway (a classic animal model for Parkinson’s disease) produces a dramatic elevation of immediate-early gene (IEG) expression in the denervated striatum. IEGs encode known transcriptional regulating factors suggesting that levodopa administration may promote long-lasting changes in the striatum that may result 139 eventually in the development of motor response complications. In this chapter, I will review the effects of both acute and chronic alterations in dopaminergic neurotransmission on striatal IEG expression and present recent evidence suggesting that IEGs may contribute to modifications in the response to levodopa possibly by modulating neuropeptide gene expression.