Many studies have suggested putative mechanisms of action for amantadine that may explain antiparkinsonian effects, but the clinical significance of any given individual mechanism remains uncertain. It seems likely that amantadine has a combination of multiple effects on both dopaminergic and nondopaminergic systems.
Dopaminergic mechanisms described for amantadine include findings of increased dopamine release (49), increased dopamine synthesis (50), inhibition of dopamine reuptake (51), and modulation of dopamine D2 receptors, producing a high-affinity state (52). This latter effect may speculatively play a role in modulating levodopa-induced dyskinesia. The relevance of these dopaminergic mechanisms is uncertain, given that studies have demonstrated that the antiparkinsonian effects can occur without changes in brain concentrations of dopamine or its metabolites (53) and without evidence for dopamine synthesis or release (54).
Other neurotransmitter effects reported with amantadine include serotoner-gic, noradrenergic (55), anticholinergic, and antiglutaminergic properties (56). The anticholinergic properties suggest a well-described antiparkinsonian interaction (57,58). In the past decade, renewed interest has arisen in the antiglutamate properties of amantadine. This can be attributed to two important clinical implications. First, it may provide a putative neuroprotective mechanism. Second, converging lines of evidence provide support to the idea that the antiglutamate properties of amantadine may be important for modulating motor complications in late-stage PD.
Amantadine possesses mild anti-NMDA properties that have led to the suggestion that the drug may contribute to a possible neuroprotective effect in PD (59,60). Glutamate excitotoxicity, mediated via persistent or sustained activation of NMDA receptors, produces an excess calcium influx, activating a cascade of molecular events leading to the common final pathway of neuronal death. Blockade of NMDA glutamate receptors has been shown to experimentally diminish the excito-toxic effects of this cascade of reactions (61,62). In cell cultures, pre-exposure of sub-stantia nigra dopaminergic neurons to glutamate antagonists provided protection when subsequently exposed to MPP+ (1-methyl-4-phenyl-pyridium ion, the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a common specific nigral toxin used to produce animal models of PD (63). Extension of these preclini-cal findings to clinical applicability in PD patients remains speculative, but probably best serves a role to stimulate future studies.
The anti-NMDA properties of amantadine have also been implicated in its role modulating motor complications such as dyskinesia (64-66). Evidence has accumulated that glutamate NMDA receptors may play a significant role in the pathogene-sis of motor complications. Loss of striatal dopamine and nonphysiologic stimulation by extrinsic levodopa, both cause sensitization of NMDA receptors on striatal medium spiny neurons in animal models (29). This sensitization may play a key role in altering normal basal ganglia responses to cortical glutaminergic input and produce the disordered motor output, which leads to motor complications. Recent studies have reported that striatal injection or systemic administration of glutamate antagonists in primate and rodent models of PD can decrease levodopa motor complications without decreasing benefits of dopaminergic treatment (7,67-70).
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