Send to

Choose Destination
See comment in PubMed Commons below
Life Sci. 2014 Aug 6;110(1):1-7. doi: 10.1016/j.lfs.2014.05.014. Epub 2014 May 29.

Effects of acute and sub-chronic L-dopa therapy on striatal L-dopa methylation and dopamine oxidation in an MPTP mouse model of Parkinsons disease.

Author information

Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA.
University of Pennsylvania, 3451 Walnut Street, Philadelphia, PA 19104, USA.
Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA. Electronic address:



The molecular mechanisms for the loss of 3,4-dihydroxyphenylalanine (l-dopa) efficacy during the treatment of Parkinson's disease (PD) are unknown. Modifications related to catecholamine metabolism such as changes in l-dopa and dopamine (DA) metabolism, the modulation of catecholamine enzymes and the production of interfering metabolites are the primary concerns of this study.


Normal (saline) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) pre-treated mice were primed with 100mg/kg of l-dopa twice a day for 14 days, and a matching group remained l-dopa naïve. l-dopa naive and primed mice received a challenge dose of 100mg/kg of l-dopa and were sacrificed 30 min later. Striatal catecholamine levels and the expression and activity of catechol-O-methyltransferase (COMT) were determined.


Normal and MPTP pre-treated animals metabolize l-dopa and DA similarly during l-dopa therapy. Administration of a challenge dose of l-dopa increased l-dopa and DA metabolism in l-dopa naïve animals, and this effect was enhanced in l-dopa primed mice. The levels of 3-OMD in MPTP pre-treated animals were almost identical to those in normal mice, which we found are likely due to increased COMT activity in MPTP pre-treated mice.


The results of this comparative study provide evidence that sub-chronic administration of l-dopa decreases the ability of the striatum to accumulate l-dopa and DA, due to increased metabolism via methylation and oxidation. This data supports evidence for the metabolic adaptation of the catecholamine pathway during long-term treatment with l-dopa, which may explain the causes for the loss of l-dopa efficacy.


1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 3,4-Dihydroxyphenyalanine (l-dopa); 3,4-Dihydroxyphenyl acetic acid (DOPAC); 3-Methoxytyramine (3-MT); 3-O-methyldopa (3-OMD); Catechol-O-methyltransferase (COMT); Dopamine (DA); Homovanillic acid (HVA); Monoamine oxidase (MAO); Parkinson's disease (PD); l-dopa-induced dyskinesia (LID)

[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center