Amantadine-sulfate has been used for several decades to treat acute
influenza A,
Parkinson's disease (PD), and acute or chronic
drug-induced dyskinesia. Several mechanisms of actions detected in vivo/in vitro including
N-methyl-D-aspartate (
NMDA)-receptor antagonism, blockage of
potassium channels,
dopamine receptor agonism, enhancement of noradrenergic release, and
anticholinergic effects have been described. We used
transcranial magnetic stimulation (TMS) to evaluate the effect of single doses of
amantadine on human motor cortex excitability in normal subjects. Using a double-blind, placebo-controlled, crossover study design, motor thresholds, recruitment curves, cortical stimulation-induced silent period (CSP), short intracortical inhibition (ICI), intracortical facilitation (ICF), and late inhibition (L-ICI) in 14 healthy subjects were investigated after oral doses of 50 and 100 mg
amantadine with single and paired pulse TMS paradigms. Spinal cord excitability was investigated by distal latencies and M-amplitudes of the abductor digiti minimi muscle. After intake of
amantadine, a significant dose-dependent decrease of ICF was noticed as well as a significant increase of L-ICI as compared to placebo. The effect on ICF and L-ICI significantly correlated with
amantadine serum levels. ICI was slightly increased after
amantadine intake, but the effect failed to be significant. Furthermore,
amantadine had no significant effects on motor thresholds, MEP recruitment curves, CSP, or peripheral excitability. In conclusion, a low dose of
amantadine is sufficient in modulating human motor cortex excitability. The decrease of ICF and increase of L-ICI may reflect glutamatergic modulation or a polysynaptic interaction of glutamatergic and
GABA-ergic circuits. Although
amantadine has several mechanisms of action, the
NMDA-receptor antagonism seems to be the most relevant effect on cortical excitability. As L-ICI can be influenced by this type of
drug, it may be an interesting parameter for studies of motor learning and use-dependent plasticity.