title: Stimulation of dopa decarboxylase activity in striatum of healthy human brain secondary to NMDA receptor antagonism with a low dose of amantadine.
abstract: 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.
authors.affiliation: McConnell Brain Imaging Center, Montreal Neurological Institute, 3801 University St., Montreal, Quebec, Canada H3A 2B4. deep@pet.mni.mcgill.ca
authors.forename: P
authors.initials: P
authors.lastname: Deep
authors.forename: A
authors.initials: A
authors.lastname: Dagher
authors.forename: A
authors.initials: A
authors.lastname: Sadikot
authors.forename: A
authors.initials: A
authors.lastname: Gjedde
authors.forename: P
authors.initials: P
authors.lastname: Cumming
mesh_terms: 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
chemical_list: 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