It appears that NMDA receptor function is suppressed during intoxication even after prolonged ethanol exposure resulting in a compensatory and selective upregulation of NMDA receptors (Hu, Follesa, & Ticku, 1996). Thus, ethanol withdrawal following chronic exposure results in increased NMDA receptor activity and elevated extracellular glutamate, especially after repeated cycles of withdrawal (Dahchour & De Witte, 1999; Gonzales, Bungay, Kilanmaa, Samson, & Rosselti, 1996; Rossetti & Carboni, 1995), postulated to contribute to CNS hyperexcitability (Becker, 1998; Littleton, 1998) and excitotoxicity (Chandler, Newsom, Sumners, & Crews, 1993; Iorio, Tabakoff, & Hoffman, 1993). Indeed, a meta-analysis of rodent microdialysis studies confirms elevated extracellular concentrations of glutamate in several brain regions that strongly correlates with alcohol withdrawal severity (Fliegel, Brand, Spanagel, & Noori, 2013).
