Figure 11. Patch configurations used to investigate ketamine blockade of the N-methyl-D-aspartate (NMDA) receptor. For the cell-attached patches, NMDA was included in the pipette solution. Ketamine was included either in the pipette or added externally to the bath solution. In the outside-out patch configuration, both ketamine and NMDA were added to the external solution. Changes in NMDA receptor activity are schematically interpreted. Our results suggest that ketamine may interact with the receptor at two potentially distinct sites: one site located within the channel pore and a second site associated with a hydrophobic domain of the protein. The binding of the agonist to the receptor is assumed to modify the binding of ketamine to both sites. Binding of ketamine at the site associated with the channel pore would decrease channel-open time (scheme 2), whereas binding to the membrane-associated site does not require the channel to be in the open state (scheme 3).