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.
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, 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.
authors.affiliation: Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: K Elisabet
authors.initials: KE
authors.lastname: Ohlin
authors.forename: Irene
authors.initials: I
authors.lastname: Sebastianutto
authors.forename: Chris E
authors.initials: CE
authors.lastname: Adkins
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lundblad
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lockman
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
mesh_terms: D000465:Algorithms; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001345:Autoradiography; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001545:Benserazide / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D002196:Capillaries / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D020820:Dyskinesias / Q000503:physiopathology; D005260:Female; D005947:Glucose / Q000378:metabolism; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D013565:Sympatholytics; D007980:Levodopa; D001545:Benserazide; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D005947:Glucose