Regulation by D2 dopamine receptors of in vivo dopamine synthesis in striata of rats and mice with experimental parkinsonism.
The effects of D2 dopamine (DA) receptor antagonism or stimulation by systemic haloperidol or quinpirole, respectively, on in vivo DA synthesis in 6-hydroxydopamine (6-OHDA)-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated black mice were assessed by measuring the rate of dihydroxyphenylalanine (DOPA) accumulation following acute inhibition of L-aromatic amino acid decarboxylase with NSD-1015. 6-OHDA and MPTP caused partial lesions of nigrostriatal input to the striatum. Dopamine synthetic capacity was preserved relative to the severity of nigrostriatal lesion over a broad range of DA depletions. An exponential increase in fractional DA synthesis (the ratio DOPA/DA) was observed with increasing DA depletion, suggesting an elevation of the DA synthetic capacity per surviving DA terminal. In both lesioned rats and mice, haloperidol caused a significant increase in fractional DA synthesis above that induced by the lesion alone, while quinpirole significantly depressed fractional DA synthesis. Our results provide evidence that nigrostriatal terminals acquire increased DA synthetic capacity as nigrostriatal lesions exceed 90%, but that the increase in fractional DA synthesis observed in partially lesioned animals is not due to a loss of autoreceptor function. Pharmacological strategies to stimulate DA synthesis and release in moderately advanced Parkinson's disease should be pursued.
Richard
M G
MG
Department of Neurology, University of Virginia School of Medicine, Charlottesville 22908.
Bennett
J P
JP
D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis*; D004873:Ergolines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D007700:Kinetics; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D019257:Quinpirole; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D012016:Reference Values
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D004873:Ergolines; D006834:Hydrazines; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D004295:Dihydroxyphenylalanine; D016627:Oxidopamine; C004297:3-hydroxybenzylhydrazine; D006220:Haloperidol; D004298:Dopamine