The dopamine transporter: importance in Parkinson's disease.
The dopamine transporter (DAT) may be the single most important determinant of extracellular dopamine concentrations. The importance of DAT in Parkinson's disease (PD) in which DAT may be reduced by 50 to 70% is unclear. We have examined the effects of methylphenidate (MPD), an inhibitor of DAT, administered alone or with levodopa, on parkinsonism measured with tapping and walking speeds, dyskinesia, subjective effects, and vital signs. MPD in oral doses of up to 0.4 mg/kg was well tolerated. Administered alone, MPD produced no objective improvement of parkinsonism. MPD, 0.4 mg/kg orally, coadministered with 2-hour levodopa infusions at 0.5 or 1.0mg/kg/hr increased the percentage of patients responding to the 0.5mg/kg/hr dose and prolonged the response to levodopa infusions as measured by tapping and walking speeds. Dyskinesia was prolonged in proportion to the increase in antiparkinson actions but severity was not increased. MPD decreased the hypotensive response to levodopa. In conclusion, MPD appeared to have no effect given alone but potentiated the effects of levodopa, particularly doses at threshold for clinical effects. These observations indicate that the residual DAT is functional in PD and is a potential target for symptomatic therapy of PD.
Nutt
John G
JG
Department of Neurology, Oregon Health and Science University, Portland, OR 97239-3098, USA. nuttj@ohsu.edu
Carter
Julie H
JH
Sexton
Gary J
GJ
D000368:Aged; D000704:Analysis of Variance; D001794:Blood Pressure / Q000187:drug effects; D015259:Dopamine Agents / Q000627:therapeutic use; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004333:Drug Administration Routes; D004357:Drug Synergism; D020820:Dyskinesias / Q000188:drug therapy; D004644:Emotions / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008774:Methylphenidate / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy; D011597:Psychomotor Performance / Q000187:drug effects; D013997:Time Factors; D016138:Walking
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human; D008774:Methylphenidate; D007980:Levodopa