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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2431958
- author
- Ohlin, Elisabet
LU
; Sebastianutto, Irene
LU
; Adkins, Chris E
; Lundblad, Cornelia
LU
; Lockman, Paul R
and Cenci Nilsson, Angela
LU
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- 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
- id
- fdd52677-03f7-48e0-8f4e-777a545a54e3 (old id 2431958)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/22406356?dopt=Abstract
- date added to LUP
- 2016-04-04 08:34:30
- date last changed
- 2022-01-29 03:37:36
@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}},
doi = {{10.1016/j.neuroimage.2012.02.066}},
volume = {{61}},
year = {{2012}},
}