TY - JOUR
T1 - Time-course and dose-response study on the effects of chronic L-DOPA administration on striatal dopamine levels and dopamine transporter following MPTP toxicity
AU - Fornai, Francesco
AU - Battaglia, Giuseppe
AU - Gesi, Marco
AU - Giorgi, Filippo S.
AU - Orzi, Francesco
AU - Nicoletti, Ferdinando
AU - Ruggieri, Stefano
PY - 2000/12/22
Y1 - 2000/12/22
N2 - Despite a long-lasting therapeutic use of L-DOPA in Parkinson's disease, doubts still remain concerning the possibility that chronic L-DOPA might accelerate 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 intermediate striatal dopamine loss by administering a low dose of MPTP (30 mg/kg); then, we treated mice chronically, for different time intervals, with a daily 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 administration. To evaluate presynaptic integrity of the nigrostriatal pathway we measured dopamine, metabolite levels, and dopamine uptake sites. In the same animals, we measured striatal serotonin levels and we analysed monoamine content in the olfactory bulb. Administration of MPTP produced a neurotoxic effect, which fully recovered in 2-3 months. Daily L-DOPA administration did not modify this recovery process. Additionally, there was no significant effect of L-DOPA in intact mice, despite a slight decrease in striatal dopamine levels at 5 and 30 days. However, this effect was neither worsened nor reproduced 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 prolonged 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.
AB - Despite a long-lasting therapeutic use of L-DOPA in Parkinson's disease, doubts still remain concerning the possibility that chronic L-DOPA might accelerate 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 intermediate striatal dopamine loss by administering a low dose of MPTP (30 mg/kg); then, we treated mice chronically, for different time intervals, with a daily 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 administration. To evaluate presynaptic integrity of the nigrostriatal pathway we measured dopamine, metabolite levels, and dopamine uptake sites. In the same animals, we measured striatal serotonin levels and we analysed monoamine content in the olfactory bulb. Administration of MPTP produced a neurotoxic effect, which fully recovered in 2-3 months. Daily L-DOPA administration did not modify this recovery process. Additionally, there was no significant effect of L-DOPA in intact mice, despite a slight decrease in striatal dopamine levels at 5 and 30 days. However, this effect was neither worsened nor reproduced 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 prolonged 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.
KW - DAT
KW - Experimental parkinsonism
KW - L-DOPA
KW - MPTP
KW - Recovery
UR - http://www.scopus.com/inward/record.url?scp=0034704291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034704291&partnerID=8YFLogxK
U2 - 10.1016/S0006-8993(00)02999-1
DO - 10.1016/S0006-8993(00)02999-1
M3 - Article
C2 - 11134595
AN - SCOPUS:0034704291
VL - 887
SP - 110
EP - 117
JO - Brain Research
JF - Brain Research
SN - 0006-8993
IS - 1
ER -