TY - JOUR

T1 - Stimulation of dopa decarboxylase activity in striatum of healthy human brain secondary to NMDA receptor antagonism with a low dose of amantadine.

AU - Deep, P

AU - Dagher, A

AU - Sadikot, A

AU - Gjedde, A

AU - Cumming, P

N1 - Copyright 1999 Wiley-Liss, Inc.

PY - 1999

Y1 - 1999

N2 - 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.

AB - 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.

M3 - Journal article

C2 - 10529725

VL - 34

SP - 313

EP - 318

JO - Synapse

JF - Synapse

SN - 0887-4476

IS - 4

ER -