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Impact of L-DOPA treatment on regional cerebral blood flow and metabolism in the basal ganglia in a rat model of Parkinson's disease.

Ohlin, Elisabet LU ; Sebastianutto, Irene LU ; Adkins, Chris E; Lundblad, Cornelia LU ; Lockman, Paul R and Cenci Nilsson, Angela LU (2012) In NeuroImage 61(1). p.228-239
Abstract
Large increases in regional cerebral blood flow (rCBF) have been measured in patients with Parkinson's disease (PD) following the administration of L-DOPA, but the underlying mechanisms have remained unknown. In this study, we have used rats with unilateral 6-hydroxydopamine (6-OHDA) lesions as a model of PD in order to compare the patterns of rCBF and regional cerebral glucose utilisation (rCGU) in chronically L-DOPA-treated 6-OHDA-lesioned and sham-lesioned rats following a final injection of L-DOPA or saline. In the same animal model, we have compared the leakage of a blood-brain barrier (BBB) tracer molecule at 60min vs. 24h following the last L-DOPA injection of a chronic treatment. All the parameters under investigation were examined... (More)
Large increases in regional cerebral blood flow (rCBF) have been measured in patients with Parkinson's disease (PD) following the administration of L-DOPA, but the underlying mechanisms have remained unknown. In this study, we have used rats with unilateral 6-hydroxydopamine (6-OHDA) lesions as a model of PD in order to compare the patterns of rCBF and regional cerebral glucose utilisation (rCGU) in chronically L-DOPA-treated 6-OHDA-lesioned and sham-lesioned rats following a final injection of L-DOPA or saline. In the same animal model, we have compared the leakage of a blood-brain barrier (BBB) tracer molecule at 60min vs. 24h following the last L-DOPA injection of a chronic treatment. All the parameters under investigation were examined with brain autoradiography following intravenous injections of specific radiotracers in awake animals ([14C]-iodoantipyrine for rCBF, [14C]-2-deoxyglucose for rCGU, and [14C]-α-aminoisobutyric acid for BBB leakage). Significant changes in rCBF and rCGU on the side ipsilateral to the 6-OHDA lesion relative to the non-lesioned side were seen at 60min ("ON") but not 24h ("OFF") following L-DOPA administration. These changes were not seen in sham-operated rats. In the output nuclei of the basal ganglia (the entopeduncular nucleus and the substantia nigra pars reticulata) both rCBF and rCGU were elevated both in acutely L-DOPA-treated rats and chronically L-DOPA-treated rats displaying dyskinesia, but did not change significantly in chronically L-DOPA-treated non-dyskinetic cases. Acutely and chronically L-DOPA-treated rats with dyskinesia exhibited increases in rCBF "ON L-DOPA" also in the motor cortex, the striatum, and the globus pallidus, but the corresponding changes in rCGU did not show the same direction, magnitude, and/or relative group differences. The uptake of a BBB tracer (studied in the striatum and the substantia nigra reticulata in chronically L-DOPA treated rats) was significantly higher ON vs. OFF L-DOPA. The present results are the first to show that the administration of L-DOPA is followed by transient and robust increases in rCBF in the dopamined enervated basal ganglia networks. This effect occurs already upon acute L-DOPA treatment and persists upon repeated drug administration in animals that develop dyskinesia. Increases in rCBF ON L-DOPA are not necessarily accompanied by enhanced glucose utilisation in the affected regions, pointing to altered mechanisms of neurovascular coupling. Finally, our results show that increases in rCBF ON L-DOPA may be accompanied by BBB hyperpermeability in the most affected regions. (Less)
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Contribution to journal
publication status
published
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in
NeuroImage
volume
61
issue
1
pages
228 - 239
publisher
Elsevier
external identifiers
  • wos:000303954600024
  • pmid:22406356
  • scopus:84859078960
ISSN
1095-9572
DOI
10.1016/j.neuroimage.2012.02.066
language
English
LU publication?
yes
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fdd52677-03f7-48e0-8f4e-777a545a54e3 (old id 2431958)
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http://www.ncbi.nlm.nih.gov/pubmed/22406356?dopt=Abstract
date added to LUP
2012-04-03 10:06:49
date last changed
2017-09-24 04:38:50
@article{fdd52677-03f7-48e0-8f4e-777a545a54e3,
  abstract     = {Large increases in regional cerebral blood flow (rCBF) have been measured in patients with Parkinson's disease (PD) following the administration of L-DOPA, but the underlying mechanisms have remained unknown. In this study, we have used rats with unilateral 6-hydroxydopamine (6-OHDA) lesions as a model of PD in order to compare the patterns of rCBF and regional cerebral glucose utilisation (rCGU) in chronically L-DOPA-treated 6-OHDA-lesioned and sham-lesioned rats following a final injection of L-DOPA or saline. In the same animal model, we have compared the leakage of a blood-brain barrier (BBB) tracer molecule at 60min vs. 24h following the last L-DOPA injection of a chronic treatment. All the parameters under investigation were examined with brain autoradiography following intravenous injections of specific radiotracers in awake animals ([14C]-iodoantipyrine for rCBF, [14C]-2-deoxyglucose for rCGU, and [14C]-α-aminoisobutyric acid for BBB leakage). Significant changes in rCBF and rCGU on the side ipsilateral to the 6-OHDA lesion relative to the non-lesioned side were seen at 60min ("ON") but not 24h ("OFF") following L-DOPA administration. These changes were not seen in sham-operated rats. In the output nuclei of the basal ganglia (the entopeduncular nucleus and the substantia nigra pars reticulata) both rCBF and rCGU were elevated both in acutely L-DOPA-treated rats and chronically L-DOPA-treated rats displaying dyskinesia, but did not change significantly in chronically L-DOPA-treated non-dyskinetic cases. Acutely and chronically L-DOPA-treated rats with dyskinesia exhibited increases in rCBF "ON L-DOPA" also in the motor cortex, the striatum, and the globus pallidus, but the corresponding changes in rCGU did not show the same direction, magnitude, and/or relative group differences. The uptake of a BBB tracer (studied in the striatum and the substantia nigra reticulata in chronically L-DOPA treated rats) was significantly higher ON vs. OFF L-DOPA. The present results are the first to show that the administration of L-DOPA is followed by transient and robust increases in rCBF in the dopamined enervated basal ganglia networks. This effect occurs already upon acute L-DOPA treatment and persists upon repeated drug administration in animals that develop dyskinesia. Increases in rCBF ON L-DOPA are not necessarily accompanied by enhanced glucose utilisation in the affected regions, pointing to altered mechanisms of neurovascular coupling. Finally, our results show that increases in rCBF ON L-DOPA may be accompanied by BBB hyperpermeability in the most affected regions.},
  author       = {Ohlin, Elisabet and Sebastianutto, Irene and Adkins, Chris E and Lundblad, Cornelia and Lockman, Paul R and Cenci Nilsson, Angela},
  issn         = {1095-9572},
  language     = {eng},
  number       = {1},
  pages        = {228--239},
  publisher    = {Elsevier},
  series       = {NeuroImage},
  title        = {Impact of L-DOPA treatment on regional cerebral blood flow and metabolism in the basal ganglia in a rat model of Parkinson's disease.},
  url          = {http://dx.doi.org/10.1016/j.neuroimage.2012.02.066},
  volume       = {61},
  year         = {2012},
}