Objective: To examine the acute effects of the NMDA receptor antagonist amantadine on motor and cognitive function in Huntington's disease (HD).

Background: Chorea in HD and in the levodopa-induced dyskinesias of PD may be clinically indistinguishable. In PD, hyperphosphorylation of NMDA receptors expressed on striatal medium spiny neurons contributes to peak-dose dyskinesias, and drugs that block these receptors can diminish chorea severity. Because these spiny neurons are the primary target of the neurodegenerative process in HD, sensitization of NMDA receptors on residual striatal neurons might also participate in the generation of motor dysfunction in HD.

Methods: To evaluate this possibility, 24 patients with HD entered a double-blind placebo-controlled crossover study of amantadine with two 2-week arms.

Results: Chorea scores were lower with amantadine (usually 400 mg/d) than placebo, with a median reduction in extremity chorea at rest of 36% (p = 0.04) for all 22 evaluable patients and of 56% in the 10 individuals with the highest plasma drug levels. Improvement correlated with plasma amantadine concentrations (p = 0.01) but not CAG repeat length. Parkinsonian rating scores did not worsen and there was no consistent change in cognitive measures. Adverse event profile was benign.

Conclusions: Results suggest that NMDA receptor supersensitivity may contribute to the clinical expression of choreiform dyskinesias in HD and that selective antagonists at that site can safely confer palliative benefit.