Stimulation of dopa decarboxylase activity in striatum of healthy human brain secondary to NMDA receptor antagonism with a low dose of amantadine.
The efficacy of amantadine in alleviating motor symptoms of Parkinson's disease may be mediated in part by stimulation of cerebral dopa decarboxylase (DDC) activity, secondary to antagonism of N-methyl-D-aspartate (NMDA) type glutamate receptors. We tested the specific hypothesis that amantadine increases the decarboxylation rate of 6-[(18)F]fluoro-L-DOPA (FDOPA), an exogenous substrate for DDC, in healthy human brain. Radioactivity concentrations in brain tissue of neurologically normal volunteers (n = 5) injected intravenously with FDOPA ( approximately 4.5 mCi) were recorded by positron emission tomography (PET) for 120 min, first in a baseline condition, and again following three consecutive days of treatment with amantadine (100 mg/day, p.o.). Data from four telencephalic regions of interest containing appreciable DDC activity were analyzed with the tissue slope-intercept plot, using cerebellar cortex as the reference tissue, to estimate a coefficient of in situ FDOPA decarboxylation (k(3)(r), min(-1)). Mean estimates of k(3)(r) were increased following amantadine treatment in caudate nucleus (+12%), putamen (+28%), ventral striatum (+27%), and frontal cortex (+9%). For an initial confidence level of 95%, paired one-sided Student's t-tests with Bonferroni correction for multiple comparisons revealed a statistically significant drug effect in ventral striatum. Present results are consistent with stimulation of DDC activity in striatum of healthy human brain secondary to NMDA receptor antagonism with a low dose of amantadine, and suggest that this response is an important mechanism underlying the anti-parkinsonian properties of amantadine. Nonetheless, PET studies in parkinsonian patients using higher, clinically effective doses of amantadine may reveal more pronounced enhancements of cerebral DDC activity.
Deep
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McConnell Brain Imaging Center, Montreal Neurological Institute, 3801 University St., Montreal, Quebec, Canada H3A 2B4. deep@pet.mni.mcgill.ca
Dagher
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Sadikot
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Gjedde
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Cumming
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D000328:Adult; D000547:Amantadine / Q000008:administration & dosage / Q000494:pharmacology*; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000378:metabolism; D004296:Dopa Decarboxylase / Q000378:metabolism*; D015259:Dopamine Agents / Q000008:administration & dosage / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005462:Fluorine Radioisotopes / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D016014:Linear Models; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014055:Tomography, Emission-Computed
D000978:Antiparkinson Agents; D015259:Dopamine Agents; D005462:Fluorine Radioisotopes; D016194:Receptors, N-Methyl-D-Aspartate; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D000547:Amantadine; D004296:Dopa Decarboxylase