Changes in the prodynorphin gene and DARPP-32 state in 6-OHDA-lesioned rats following long-term treatment with l-dopa

Recent evidence revealed a crucial role of direct striatal pathway pathophysiological over-activation in the pathogenesis of l-dopa-induced dyskinesias (LID). In order to explore the potential mechanism(s) involved in the over-activation of direct striatal pathways, this study was designed to examine changes in prodynorphin (PDyn) gene expression as well as phosphorylation of dopamine and 32 kDa cAMP-regulated phosphoprotein (DARPP-32) in rats with LID using in situ hybridization and immunoblotting. Our data demonstrated significantly increased levels of PDyn mRNA and phospho-Thr-34 DARPP-32 and significantly decreased phospho-Thr-75 DARPP-32 in LID rats compared with control and l-dopa treated groups. Following treatment of the non-competitive NMDA receptor antagonist dizocilpine (MK-801), the LID-induced changes in PDyn mRNA, phospho-Thr-34 DARPP-32 and phospho-Thr-75 DARPP-32 were largely reversed. Collectively, these findings suggested that changes of the DARPP-32 phosphorylation state may be important for over-activation of the direct pathway.