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The Journal of Neuroscience, March 30, 2005, 25(13):3312-3322; doi:10.1523/JNEUROSCI.4262-04.2005

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Cellular/Molecular
Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

Thomas A. Blanpied,¹ Richard J. Clarke,^1,2 and Jon W. Johnson^1,2

¹Department of Neuroscience and ²Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

The channel of NMDA receptors is blocked by a wide variety of drugs. NMDA receptor channel blockers include drugs of abuse that induce psychotic behavior, such as phencyclidine, and drugs with wide therapeutic utility, such as amantadine and memantine. We describe here the molecular mechanism of amantadine inhibition. In contrast to most other described channel-blocking molecules, amantadine causes the channel gate of NMDA receptors to close more quickly. Our results confirm that amantadine binding inhibits current flow through NMDA receptor channels but show that its main inhibitory action at pharmaceutically relevant concentrations results from stabilization of closed states of the channel. The surprising variation in the clinical utility of NMDA channel blockers may in part derive from their diverse effects on channel gating.

Key words: NMDA; Parkinson; synaptic transmission; channel block; glutamate; single-channel patch-clamp

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Received Oct 13, 2004; revised February 16, 2005; accepted February 16, 2005.

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