title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Marquitta L
authors.initials: ML
authors.lastname: Smith
authors.affiliation: University of Pennsylvania, 3451 Walnut Street, Philadelphia, PA 19104, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: King
authors.affiliation: Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Lemuel
authors.initials: L
authors.lastname: Dent
authors.affiliation: Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Mackey
authors.affiliation: Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Gladson
authors.initials: G
authors.lastname: Muthian
authors.affiliation: Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Brenya
authors.initials: B
authors.lastname: Griffin
authors.affiliation: Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA. Electronic address: ccharlton@mmc.edu.
authors.forename: Clivel G
authors.initials: CG
authors.lastname: Charlton
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D007980:Levodopa / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D002394:Catechol O-Methyltransferase; D004298:Dopamine
keywords: 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)