Dystonia, the third most common movement disorder after tremor and Parkinson's disease, is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Human functional imaging studies associate cerebellar hyperactivity with dystonia. Fan et al. explored the relationship between abnormal cerebellar excitation and dystonia to determine whether a nonspecific increase in excitability or specific pathways were involved with dystonia. Nonspecific increase in cerebellar excitability (induced by picrotoxin) was not associated with dystonia. Instead, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (glutamate) receptor activation was necessary to evoke dystonia. AMPA agonists induced, antagonists reduced, and AMPA desensitization reduced dystonia. AMPA antagonists also reduced dystonia in the dystonic mouse mutant tottering, suggesting a link in other genetic models of dystonia. These animal studies, coupled with the results from imaging and blood flow studies, suggest a novel hypothesis that the increase in cerebellar signal observed in neuroimaging studies of patients with dystonia may be an indirect reflection of abnormal AMPA receptor activation. The obvious correlate of this hypothesis is that reducing AMPA receptor signaling by directly blocking AMPA receptors, promoting AMPA receptor desensitization or negative allosteric modulation of AMPA receptors, may prove useful in the treatment of dystonia.
See article at J Pharmacol Exp Ther 2012, 340:733–741.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics