Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with eith...

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Published in:	Neuropsychopharmacology (New York, N.Y.) Vol. 34; no. 12; pp. 2477 - 2488
Main Authors:	LINDGREN, Hanna S, ELISABET OHLIN, K, CENTI, M. Angela
Format:	Journal Article
Language:	English
Published:	Basingstoke Nature Publishing Group 01-11-2009
Subjects:	2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - pharmacology Adult and adolescent clinical studies Aminoacetonitrile - analogs & derivatives Aminoacetonitrile - pharmacology Angiogenesis Animals Antiparkinson Agents - pharmacology Basal Ganglia - blood supply Basal Ganglia - drug effects Basal Ganglia - physiology Basic Medicine Benzazepines - pharmacology Biological and medical sciences Brain Bromocriptine - pharmacology Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Disease Disease Models, Animal Dopamine Dopamine Agents - pharmacology Dopamine D2 Receptor Antagonists Drug dosages Dyskinesia Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors Female Levodopa - pharmacology Medical and Health Sciences Medical sciences Medicin och hälsovetenskap Medicinska och farmaceutiska grundvetenskaper Neovascularization, Pathologic - chemically induced Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - physiopathology Nervous system (semeiology, syndromes) Nervous system as a whole Neurology Neurosciences Neurovetenskaper Organic mental disorders. Neuropsychology Oxidopamine Parkinson's disease Parkinsonian Disorders - chemically induced Parkinsonian Disorders - drug therapy Parkinsonian Disorders - physiopathology Pathophysiology Protease Inhibitors - pharmacology Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry Rats Rats, Sprague-Dawley Receptors, Dopamine D1 - agonists Receptors, Dopamine D1 - antagonists & inhibitors Receptors, Dopamine D1 - metabolism Receptors, Dopamine D2 - agonists Receptors, Dopamine D2 - metabolism Salicylamides - pharmacology Sweden Animal model Agonist Rat Central nervous system Parkinson disease 6-OHDA Oxidopamine Blood brain barrier Encephalon Involuntary movement Angiogenesis Degenerative disease Levodopa Neurological disorder DOPA Dyskinesia blood-brain barrier Nervous system diseases Dopamine receptor Rodentia Sympathomimetic Antiparkinson agent Motor control Cerebral disorder Vertebrata Mammalia D2 Dopamine receptor dopamine receptors Animal Central nervous system disease Pharmacokinetics Adrenergic receptor Extrapyramidal syndrome
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Summary:	Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis can be blocked by co-treatment with either a D1- or a D2 receptor antagonist (SCH23390 and eticlopride, respectively), or by an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (SL327). L-DOPA, but not bromocriptine, induced dyskinesia, which was associated with endothelial proliferation, upregulation of immature endothelial markers (nestin) and downregulation of endothelial barrier antigen in the striatum and its output structures. At a dose inducing dyskinesia (1.5 mg/kg/day), SKF38393 elicited angiogenic changes similar to L-DOPA. Antagonism of D1- but not D2 class receptors completely suppressed both the development of dyskinesia and the upregulation of angiogenesis markers. In fact, L-DOPA-induced endothelial proliferation was markedly exacerbated by low-dose D2 antagonism (0.01 mg/kg eticlopride). Inhibition of ERK1/2 by SL327 attenuated L-DOPA-induced dyskinesia and completely inhibited all markers of angiogenesis. These results highlight the specific link between treatment-induced dyskinesias and microvascular remodeling in the dopamine-denervated brain. L-DOPA-induced angiogenesis requires stimulation of D1 receptors and activation of ERK1/2, whereas the stimulation of D2 receptors seems to oppose this response.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0893-133X 1740-634X 1740-634X
DOI:	10.1038/npp.2009.74