Does treatment with dopamine agonists affect utilization of exogenous levodopa in the parkinsonian striatum?
When the nigrostriatal projection is partially destroyed in Parkinson's disease, remaining neurons fire more rapidly and accelerate synthesis and release of dopamine (DA) from endogenous tyrosine and levodopa. It was suggested that such surviving hyperactive nigral neurons can also enhance the utilization of exogenous levodopa and generate adequate amounts of functional dopamine molecules to correct the reduced nigrostriatal neurotransmission. DA agonists stimulate presynaptic DA receptors and suppress nigrostriatal firing rates. Many parkinsonians are treated with a combination of DA agonists and levodopa. This could theoretically suppress both discharge of surviving dopaminergic neurons and their ability to convert exogenous levodopa to dopamine. To test this possibility, rats were injected i.p. with lisuride, bromocriptine or apomorphine alone or one hour after levodopa and decapitated one hour later. The DA agonists suppressed striatal DOPAC and DOPAC/DA ratios indicating attenuation of basic DA turnover. DA agonists given with levodopa did not decrease the levodopa-induced elevations in striatal levodopa, DA and DOPAC. Findings suggest that agonists do not affect entry of levodopa from the circulation into brain and do not alter striatal generation of DA from exogenous levodopa despite inhibition of nigrostriatal firing. Therefore, utilization of levodopa does not seem to depend on the state of discharge rates of nigral neurons and effect of levodopa and DA agonists in Parkinson's disease is additive.
Melamed
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Department of Neurology, Beilinson Medical Center, Petah Tiqva, Israel.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism*; D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D018491:Dopamine Agonists / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D007980:Levodopa / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa