Time-course and dose-response study on the effects of chronic L-DOPA administration on striatal dopamine levels and dopamine transporter following MPTP toxicity

Despite a long-lasting therapeutic use of L-DOPA in Parkinson's disease, do ubts still remain concerning the possibility that chronic L-DOPA might acce lerate the progression of this movement disorder. To address this point, in the present study we examined the effects of chronic L-DOPA administration either in intact or MPTP-treated parkinsonian mice. We produced an interme diate striatal dopamine loss by administering a low dose of MPTP (30 mg/kg) ; then, we treated mice chronically, for different time intervals, with a d aily dose of L-DOPA (50 mg/kg). In particular, to study the time-course of the effects of L-DOPA on the recovery of nigrostriatal dopamine axons, mice were sacrificed at 5, 30, 60, and 90 days after a daily L-DOPA administrat ion. To evaluate presynaptic integrity of the nigrostriatal pathway we meas ured dopamine, metabolite levels, and dopamine uptake sites. Ln the same an imals, we measured striatal serotonin levels and we analysed monoamine cont ent in the olfactory bulb. Administration of MPTP produced a neurotoxic eff ect, which fully recovered in 2-3 months. Daily L-DOPA administration did n ot modify this recovery process. Additionally, there was no significant eff ect of L-DOPA in intact mice? despite a slight decrease in striatal dopamin e levels at 5 and 30 days. However, this effect was neither worsened nor re produced by administering higher doses of L-DOPA (up to 400 mg/kg) for the same amount of time. These data rule out neurotoxic effects induced by prol onged L-DOPA administration, both in intact and MPTP-treated mice. Moreover , administration of L-DOPA does not change the recovery process which takes place after a nigrostriatal lesion. (C) 2000 Elsevier Science B.V. All rig hts reserved.