L-DOPA-derived extracellular dopamine in the striatum with dopaminergic denervation: role of serotonergic neurons in l-DOPA metabolism

摘要

In order to determine the state of dopamine (DA) derived from exogenously administered l-3,4-dihydroxyphenylalanine (l-DOPA) in the striatum of Parkinson's disease, we have applied an in vivo brain microdialysis method to rats with dopaminergic denervation with 6-hydroxydopamine (6-OHDA), the rat model of Parkinson's disease, and measured extracellular DA levels in the striatum after l-DOPA administration. We obtained the following results: (1) Inhibitory effect of the potent D2 agonist quinpirole on L-DOPA-derived extracellular DA was not detected in the denervated striatum; (2) reserpine pretreatment greatly reduced L-DOPA-derived extracellular DA; (3) additional serotonergic denervation to rats with dopaminergic denervation induced a significant reduction in l-DOPA-derived extracellular DA; and (4) activation of 5-hydroxytryptamine (serotonin) (5-HT)1A receptors attenuated an increase in L-DOPA-derived extracellular DA. These results suggest that the conversion of exogenous l-DOPA to DA and the storage andrelease of converted DA occur in serotonergic nerve terminals when dopaminergic neurons are denervated. It is possible that serotonergic neurons play a critical role in the therapeutic effect of l-DOPA in Parkinson's disease. ?2003 Elsevier Science B.V. All rights reserved.