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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.
J Neurochem. 2010 Mar; 112(6):1465-76.JN

Abstract

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.

Authors+Show Affiliations

Basal Ganglia Pathophysiology, Department of Experimental Medical Science, Lund University, Lund, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20050978

Citation

Lindgren, Hanna S., et al. "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." Journal of Neurochemistry, vol. 112, no. 6, 2010, pp. 1465-76.
Lindgren HS, Andersson DR, Lagerkvist S, et al. 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. J Neurochem. 2010;112(6):1465-76.
Lindgren, H. S., Andersson, D. R., Lagerkvist, S., Nissbrandt, H., & Cenci, M. A. (2010). 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. Journal of Neurochemistry, 112(6), 1465-76. https://doi.org/10.1111/j.1471-4159.2009.06556.x
Lindgren HS, et al. 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. J Neurochem. 2010;112(6):1465-76. PubMed PMID: 20050978.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Lindgren,Hanna S, AU - Andersson,Daniel R, AU - Lagerkvist,Sören, AU - Nissbrandt,Hans, AU - Cenci,M Angela, Y1 - 2009/12/24/ PY - 2010/1/7/entrez PY - 2010/1/7/pubmed PY - 2010/5/1/medline SP - 1465 EP - 76 JF - Journal of neurochemistry JO - J Neurochem VL - 112 IS - 6 N2 - 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. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/20050978/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_ L2 - https://doi.org/10.1111/j.1471-4159.2009.06556.x DB - PRIME DP - Unbound Medicine ER -