Widespread Monoaminergic Dysregulation of Both Motor and Non-Motor Circuits in Parkinsonism and Dyskinesia.
Beyond dopamine (DA) loss, Parkinson's disease is associated with many other monoamine alterations. While some monoaminergic systems benefit from l-3,4-dihydroxyphenylalanine (l-Dopa) treatment, others seem to be further altered, contributing to dyskinesia and nonmotor symptoms. Surprisingly, the different contributions of parkinsonism and l-Dopa treatment on monoaminergic changes remain largely unknown. Here, both the consequences of vehicle or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure and the subsequent effects of acute or chronic l-Dopa treatment were evaluated in macaques. Monoamine levels were measured in the putamen, the motor and prefrontal cortices, the hippocampus, and the amygdala using postmortem high-pressure liquid chromatography. In normal monkeys, l-Dopa treatment increased DA in the prefrontal cortex and hippocampus, but decreased serotonin levels in motor domains. Chronic l-Dopa treatment elevated monoamine levels in the prefrontal cortex, hippocampus, and amygdala in both normal and MPTP-treated monkeys. A substantial increase in DA levels in these regions, paralleled by a decrease in serotonin concentrations were related with dyskinesia severity, demonstrating that major changes in monoamine release also occur in nonmotor regions. Such monoaminergic dysregulation in limbic domains may also directly contribute to the expression of motor complications, such as dyskinesia, by impairing integrative processes upstream from motor execution.
Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
Michel
M
Engeln
Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
Philippe
P
De Deurwaerdère
Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing 100101, China.
Qin
Q
Li
Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing 100101, China.
Erwan
E
Bezard
Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
Pierre-Olivier
PO
Fernagut
D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000473:pathology*; D005260:Female; D007980:Levodopa / Q000009:adverse effects; D020267:MPTP Poisoning / Q000188:drug therapy / Q000473:pathology*; D008253:Macaca mulatta; D009434:Neural Pathways / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
D000978:Antiparkinson Agents; D015306:Biogenic Monoamines; D007980:Levodopa
MPTP; Parkinson's disease; limbic; monkey; serotonin