Ethanol inhibition of NMDA receptor (NMDAR) function has been studied in depth, but the details of the ethanol-receptor interaction are poorly understood (Bell et al., 2016). Interactions appear to involve the N-terminal and transmembrane 3 (TM3) domains of receptor subunits, as mutation of these sites alters ethanol inhibition of NMDARs (Smothers et al., 2013). Based on this work, a bottom-up approach using an ethanol-resistant TM3 domain mutation (Ronald et al., 2001; Smothers and Woodward, 2006, 2016) found altered ethanol-associated behaviors (den Hartog et al., 2013). Further investigation is needed to fully understand how this mutation and other alterations in NMDAR function can affect pharmacological and behavioral effects of ethanol.
