Persistent changes in striatal gene expression induced by long-term L-DOPAtreatment in a rat model of Parkinson's disease

Current knowledge of the molecular changes induced by dopamine denervation and subsequent treatment with L-DOPA is based on studies performed on relat ively 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 mRN As and FosB/Delta FosB-related proteins. Unilaterally 6-hydroxydopamine-les ioned rats were treated with therapeutical doses Of L-DOPA for one year (lo ng-term group) or a few weeks (short-term group). Age-matched lesioned rats received injections of vehicle or bromocriptine, an antiparkinsonian compo und which does not produce dyskinesia when administered de novo. The lesion -induced up-regulation of preproenkephalin mRNA expression persisted at mor e than one year postlesion, and was unaffected by the pharmacological treat ments applied. L-DOPA, but not bromocriptine, induced high striatal levels of FosB/Delta FosB immunoreactivity and prodynorphin mRNA, and these did no t differ between short-term and longterm L-DOPA-treated rats. The present d ata provide the first demonstration that L-DOPA maintains high striatal lev els of fosB and prodynorphin gene expression during a prolonged course of t reatment, which simulates the clinical practice in Parkinson's disease more closely than the short-treatment paradigms studied thus far.