Mechanism of over-activation in direct pathway mediated by dopamine D1 receptor in rats with levodopa-induced dyskinesias

Objective To study the changes of prodynorphin (PDyn) gene expression and dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) phosphorylation in rats with levodopa-induced dyskinesias (LID),and to explore the mechanism of over-activation in direct pathway mediated by dopamine D1 receptor. Methods Parkinson’s disease (PD) rats were received levodopa (10 mg/kg,i.p.) for 28 d to get the LID rats. According to the behavior scale,LID rats were divided into mild (n=8) and severe (n=16) groups. On day 29,8 rats in severe LID group were given an acute intraperitoneal injection of MK-801 (0.1 mg/kg) 15 min before levodopa treatment (MK-801 group,n=8). The normal rats received same course and dosage of levodopa as the control group (n=8). Hybridization in situ was used to measure the expression of PDyn mRNA in striatum. Protein and mRNA levels of total DARPP-32 and phospho-Thr-34 DARPP-32 level were measured by immunoblotting and RT-PCR,respectively. Results The levels of PDyn mRNA and phospho-Thr-34 DARPP-32 increased significantly in LID rats compared with control rats (P<0.01),and they also increased markedly in severe LID group compared with mild group (P<0.01). Conclusion Phospho-Thr-34 DARPP-32 level was increased in LID rats,which contributed to the over-activation of direct pathway mediated by dopamine D1 receptor.