Intrastriatal inhibition of aromatic amino acid decarboxylase prevents l-DOPA-induced dyskinesia: a bilateral reverse in vivo microdialysis study in 6-hydroxydopamine lesioned rats.
l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia consists of involuntary choreiform and dystonic movements. Here we report whether intrastriatal l-DOPA itself is able to trigger dyskinetic behavior and which role the neurotransmitter dopamine (DA) and its metabolites play. Intrastriatal l-DOPA as well as DA administration at the 6-hydroxydopamine (6-OHDA) lesioned side led to a significant appearance of dyskinetic behavior, whereas DA metabolites were ineffective. Intrastriatal inhibition of the enzyme aromatic amino acid decarboxylase (AADC) by benserazide prevented the appearance of l-DOPA-induced dyskinetic movements at the lesioned side. Principle component analysis of DA and DA metabolite levels with dyskinesia scores after l-DOPA/benserazide (6/15 mg/kg) administration indicated a significant correlation only for DA, whereas DA metabolites did not show any significant correlation with the occurrence of dyskinetic behavior. We conclude that intrastriatal l-DOPA itself is not able to induce dyskinetic movements, whereas the increase of intrastriatal DA levels is instrumental for l-DOPA- and DA-induced dyskinetic behavior.
Buck
Kerstin
K
Department CNS Research, Boehringer Ingelheim Pharma GmbH and Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany.
Ferger
Boris
B
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001545:Benserazide / Q000627:therapeutic use; D001930:Brain Injuries / Q000139:chemically induced / Q000188:drug therapy; D003342:Corpus Striatum / Q000201:enzymology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000009:adverse effects*; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000473:pathology* / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D017551:Microdialysis; D016627:Oxidopamine; D051381:Rats; D017208:Rats, Wistar
D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D001545:Benserazide; D016627:Oxidopamine; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine; D006719:Homovanillic Acid