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

Neuroimage. 2012 May 15;61(1):228-39. doi: 10.1016/j.neuroimage.2012.02.066. Epub 2012 Mar 3.


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, rats with unilateral 6-hydroxydopamine (6-OHDA) lesions were used to compare patterns of rCBF and regional cerebral glucose utilisation (rCGU) in chronically L-DOPA-treated subjects following a final injection of L-DOPA or saline. The same animal model was used to the leakage of a blood-brain barrier (BBB) tracer molecule at 60 min 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 60 min ("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 dopamine-denervated basal ganglia. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Antiparkinson Agents / pharmacology*
  • Autoradiography
  • Basal Ganglia / drug effects
  • Basal Ganglia / metabolism*
  • Behavior, Animal / drug effects
  • Benserazide / pharmacology
  • Blood-Brain Barrier / drug effects
  • Capillaries / metabolism
  • Cerebrovascular Circulation / drug effects*
  • Dyskinesias / physiopathology
  • Female
  • Glucose / metabolism
  • Immunohistochemistry
  • Intermediate Filament Proteins / metabolism
  • Levodopa / pharmacology*
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Oxidopamine
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / drug therapy*
  • Parkinson Disease, Secondary / physiopathology*
  • Permeability / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Sympatholytics
  • Tyrosine 3-Monooxygenase / metabolism


  • Antiparkinson Agents
  • Intermediate Filament Proteins
  • Nerve Tissue Proteins
  • Nes protein, rat
  • Nestin
  • Sympatholytics
  • Levodopa
  • Benserazide
  • Oxidopamine
  • Tyrosine 3-Monooxygenase
  • Glucose