l-DOPA-induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson's disease: temporal and quantitative relationship to the expression of dyskinesia

• Published in: Journal of neurochemistry Vol. 112; no. 6; pp. 1465 - 1476
• Main Authors: Lindgren, Hanna S, Andersson, Daniel R, Lagerkvist, Sören, Nissbrandt, Hans, Cenci, M. Angela
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-03-2010; Blackwell Publishing Ltd; Wiley-Blackwell
• Subjects: 5‐hydroxytryptamine; Animals; Basic Medicine; Biological and medical sciences; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dopamine - metabolism; dopamine replacement therapy; dopamine transporter; Dyskinesia, Drug-Induced - physiopathology; Female; Fysiologi; L-dopa; levodopa; Levodopa - adverse effects; Levodopa - therapeutic use; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Microdialysis; monoamine; motor complications; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurobiology; Neurology; Neurons; Neurosciences; Neurovetenskaper; Oxidopamine - toxicity; Parkinson Disease - drug therapy; Parkinson Disease - etiology; Parkinson Disease - pathology; Parkinson's disease; Physiology; Rats; Rats, Sprague-Dawley; Reaction kinetics; Rodents; serotonin; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Time Factors; Animal model; Rat; 5-hydroxytryptamine; Central nervous system; Parkinson disease; dopamine replacement therapy; Abnormal movement; motor complications; Encephalon; Involuntary movement; levodopa; monoamine; Degenerative disease; Neurological disorder; Dyskinesia; Drug; Nervous system diseases; Dopamine; Rodentia; Basal ganglion; Corpus striatum; Catecholamine; Metabolism; Cerebral disorder; Vertebrata; Chronic; Mammalia; Locus niger; dopamine transporter; microdialysis; Animal; Central nervous system disease; Neurotransmitter; Lesion; Extrapyramidal syndrome
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06556.x

J. Neurochem. (2010) 112, 1465-1476. l-DOPA-induced dyskinesia in Parkinson's disease is associated with large increases in brain dopamine (DA) levels following drug dosing, but the precise significance of this phenomenon is not understood. Here we compare DA efflux and metabolism in the striatum and the substantia nigra in dyskinetic and non-dyskinetic animals following a standard dose of l-DOPA. Rats with 6-hydroxydopamine lesions were treated chronically with l-DOPA, monitored on the abnormal involuntary movements scale, and then subjected to intracerebral microdialysis under freely-moving conditions. Following s.c. l-DOPA injection, peak extracellular DA levels in both striatum and substantia nigra were about twice as large in dyskinetic animals compared to non-dyskinetic rats. This effect was not attributable to differences in DOPA levels or DA metabolism. The larger DA efflux in dyskinetic animals was blunted by 5-HT1A/5-HT1B receptor agonists and tetrodotoxin infusion, reflecting release from serotonin neurons. Striatal levels of serotonin and its main metabolite, 5-hydroxyindolacetic acid were indeed elevated in dyskinetic animals compared to non-dyskinetic rats, indicating a larger serotonergic innervation density in the former group. High DA release was, however, not sufficient to explain dyskinesia. The 'abnormal involuntary movements output' per unit concentration of striatal extracellular DA was indeed much larger in dyskinetic animals compared to non-dyskinetic cases at most time points examined. The present results indicate that both a high DA release post- l-DOPA administration and an increased responsiveness to DA must coexist for a full expression of dyskinesia.