Pre-synaptic dopaminergic compensation after moderate nigrostriatal damage in non-human primates.
Despite a dramatic loss of nigrostriatal dopaminergic neurons in Parkinson's disease, clinical symptoms only arise with 70-80% reduction of striatal dopamine. The mechanisms responsible for this functional compensation are currently under debate. Although initial studies showed an enhanced pre-synaptic dopaminergic function with nigrostriatal degeneration, more recent work suggests that functional compensation is not dopamine-mediated. To address this issue, we used cyclic voltammetry to directly measure endogenous dopamine release from striatal slices of control monkeys and animals with a moderate or severe MPTP-induced dopaminergic lesion. The moderately lesioned monkeys were asymptomatic, while the severely lesioned animals were parkinsonian. In monkeys with a moderate lesion, a 300% increase was obtained in endogenous striatal dopamine release. In contrast, in striatal slices from severely lesioned animals, a small % of evoked dopamine signals were similar in amplitude to control while the greater majority were undetectable. These findings suggest that pre-synaptic dopaminergic compensation develops in residual dopaminergic terminals with moderate lesioning, but that this response is lost with severe nigrostriatal damage. Such an interpretation is supported by the results of dopamine turnover studies. This enhanced pre-synaptic dopaminergic activity may be important in maintaining normal motor function during the initial stages of Parkinson's disease.
Perez
Xiomara A
XA
The Parkinson's Institute, Sunnyvale, California 94085, USA.
Parameswaran
Neeraja
N
Huang
Luping Z
LZ
O'Leary
Kathryn T
KT
Quik
Maryka
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D012453:Saimiri; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine