神経治療学
Online ISSN : 2189-7824
Print ISSN : 0916-8443
ISSN-L : 2189-7824
教育講演
Levodopa誘発ジスキネジアの病態機序と治療
冨山 誠彦
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ジャーナル フリー

2020 年 37 巻 4 号 p. 517-520

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Chronic levodopa treatment often leads to problematic levodopa–induced dyskinesia (LID) in patients with Parkinson disease. There are two distinct factors that lower LID threshold, dopaminergic denervation and repeated L–dopa treatment. The emergence of LID is determined by excessive GABA release from terminals of striatal spiny projection neurons composing the direct pathway (dSPN) into the output nuclei. The GABA release from dSPN receives negative feedback by GABAb receptors located on terminals of dSPN. Dopaminergic denervation disables the negative feedback for the GABA release. Then, in the brains with severe dopaminergic denervation, D1 receptor stimulation to dSPN triggers excessive GABA release into the output nuclei. Thus, dopaminergic denervation itself lowers dyskinesia threshold. In addition, along with dopamine neuron loss, serotonin neurons become to convert L–dopa to dopamine and release the dopamine into the striatum. However, unlike dopamine neurons, serotonin neurons cannot control synaptic dopamine levels because they lack D2 receptors and dopamine transporters. As the results, the striatal dopamine levels fluctuate markedly after L–dopa intake, resulting in pulsatile stimulation of dopamine receptors in the striatum. The pulsatile stimulation makes corticostsital synapses at dSPN more sensitive and induces hyperactivity of signal transduction of dSPN. Then, GABA synthesis rises in dSPN after L–dopa and repeated L–dopa treatment gradually increases GABA pool in axon terminals of dSPN. Thus, L–dopa treatment gives a rise to a gradual increase in GABA release into GPi/SNr, reflecting worsening of dyskinesia and lowering of LID threshold. That is to say, the priming of dyskinesia is the GABA storage process, and the emergence of dyskinesia is determined by the amount of the GABA release triggered by each L–dopa intake.

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