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.

Variations of Aripiprazole-Induced Dyskinesia Existing with Concurrent Use of Amantadine and an Anticholinergic Agent in an Elderly Patient

“…A partial dopamine agonist has less activity than natural dopamine and needs reduced acetylcholine function to maintain a balance between these two neurotransmitters and thereby prevent involuntary movement. The dopaminergic tone (associated with amantadine) and anticholinergic tone (associated with trihexyphenidyl) in the nigrostriatal dopamine system modify the functional manifestation of aripiprazole and promote D 2 receptor activation, explaining the emergence of TD in this patient, as indicated in previous reports 1, 3,5,9 . Third, a decreased brain neuron reserve makes elderly people sensitive to the adverse neurological effect of a dopamine partial agonist 10 .…”

Modulation of Human Motor Cortex Excitability by Single Doses of Amantadine

“…In addition, the effect of AMA on the DA system in in vitro and in vivo experiments is an increased striatal DA activity (Shannon et al, 1987;Deep et al, 1999;Moresco et al, 2002).…”

Motor-learning Impairment by Amantadine in Healthy Volunteers

“…The latter finding favors the idea that the effect of amantadine is not related to its anticholinergic action exerted either directly (Nastuk et al, 1976), or indirectly through inhibition of the NMDA-evoked acetylcholine release (Stoof et al, 1992). Finally, as suggested by positron emission tomography studies (Deep et al, 1999;Moresco et al, 2002), amantadine may exert an indirect dopaminergic effect by stimulating dopa decarboxylase activity or dopamine synthesis in the brain. However, the latter proposal cannot explain our finding because amantadine at therapeutic doses does not substantially increase extracellular brain levels of dopamine or its metabolites (Stoof et al, 1992;Quack et al, 1995).…”