The roles of striatal serotonin and L -amino-acid decarboxylase on L-DOPA-induced Dyskinesia in a Hemiparkinsonian rat model.
The administration of L: -DOPA is the standard treatment for Parkinson's disease (PD). However, the symptomatic relief provided by long-term administration may be compromised by L: -DOPA-induced dyskinesia (LID) that presents as adverse fluctuations in motor responsiveness and progressive loss of motor control. In the later stages of PD, raphestriatal serotonin neurons compensate for the loss of nigrostriatal dopamine (DA) neurons by converting and releasing DA derived from exogenous L: -DOPA. Since the serotonin system does not have an autoregulatory mechanism for DA, raphe-mediated striatal DA release may fluctuate dramatically and precede the development of LID. The 6-hydroxydopamine lesioned rats were treated with L: -DOPA (6 mg/kg) and benserazide (15 mg/kg) daily for 3 weeks to allow for the development of abnormal involuntary movement score (AIMs). In rats with LID, chronic treatment with L: -DOPA increased striatal DA levels compared with control rats. We also observed a relative increase in the expression of striatal L: -amino-acid decarboxylase (AADC) in LID rats, even though tyrosine hydroxylase (TH) expression did not increase. The administration of L: -DOPA also increased striatal serotonin immunoreactivity in LID rats compared to control rats. Striatal DA and 5-hydroxytryptamine (5-HT) levels were negatively correlated in L: -DOPA-treated rats. These results of this study reveal that 5-HT contributes to LID. Striatal DA positively influences LID, while 5-HT is negatively associated with LID. Finally, we suggest that by strategic modification of the serotonin system it may be possible to attenuate the adverse effects of chronic L: -DOPA therapy in PD patients.
Department of Pharmacology, College of Medicine, Hanyang University, 133-791, Seoul, Korea.
Sukju
S
Gil
Changhwan
C
Park
Jeongeun
J
Lee
Hyunchul
H
Koh
D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism*; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000150:complications* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D007980:Levodopa; D009068:Movement; D017072:Neostriatum / Q000201:enzymology* / Q000473:pathology; D016627:Oxidopamine; D010300:Parkinson Disease / Q000150:complications* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D012701:Serotonin; D007980:Levodopa; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001142:Aromatic-L-Amino-Acid Decarboxylases