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 dis ease 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 inc reases the decarboxylation rate of 6-[ F-18]fluoro-L-DOPA (FDOPA), an exoge nous substrate for DDC, in healthy human brain. Radioactivity concentration s in brain tissue of neurologically normal volunteers (n = 5) injected intr avenously with FDOPA (similar to 4.5 mCi) were recorded by positron emissio n tomography (PET) for 120 min, first in a baseline condition, and again fo llowing three consecutive days of treatment with amantadine (100 mg/day, p. o.). Data from four telencephalic regions of interest containing appreciabl e DDC activity were analyzed with the tissue slope-intercept plot, using ce rebellar cortex as the reference tissue, to estimate a coefficient of in si tu FDOPA decarboxylation (k(3)(r), min(-1)). Mean estimates of k(3)(r) were increased following amantadine treatment in caudate nucleus (+12%), putame n (+28%), ventral striatum (+27%), and frontal cortex (+9%). For an initial confidence level of 95%, paired one-sided Student's t-tests with Bonferron i correction for multiple comparisons revealed a statistically significant drug effect in ventral striatum. Present results are consistent with stimul ation of DDC activity in striatum of healthy human brain secondary to NMDA receptor antagonism with a low dose of amantadine, and suggest that this re sponse is an important mechanism underlying the anti-parkinsonian propertie s of amantadine. Nonetheless, PET studies in parkinsonian patients using hi gher, clinically effective doses of amantadine may reveal more pronounced e nhancements of cerebral DDC activity. (C) 1999 Wiley-Liss, Inc.