Current knowledge of the molecular changes induced by dopamine denervation and subsequent treatment with l-DOPA is based on studies performed on relatively acute and young animal models of parkinsonism. It is highly warranted to ask how well these models simulate the state of chronic denervation and sustained l-DOPA pharmacotherapy which are typical of advanced Parkinson's disease. This study investigates the effects of time postdenervation and l-dopa treatment duration on the striatal expression of opioid precursor mRNAs and FosB/ΔFosB-related proteins. Unilaterally 6-hydroxydopamine-lesioned rats were treated with therapeutical doses of l-DOPA for one year (long-term group) or a few weeks (short-term group). Age-matched lesioned rats received injections of vehicle or bromocriptine, an antiparkinsonian compound which does not produce dyskinesia when administered de novo. The lesion-induced up-regulation of preproenkephalin mRNA expression persisted at more than one year postlesion, and was unaffected by the pharmacological treatments applied. l-DOPA, but not bromocriptine, induced high striatal levels of FosB/ΔFosB immunoreactivity and prodynorphin mRNA, and these did not differ between short-term and long-term l-DOPA-treated rats. The present data provide the first demonstration that l-DOPA maintains high striatal levels of fosB and prodynorphin gene expression during a prolonged course of treatment, which simulates the clinical practice in Parkinson's disease more closely than the short-treatment paradigms studied thus far.