N-methyl-d-aspartate glutamatergic receptors and associated intracellular signaling molecules adapt to the reoccurring presence of alcohol, facilitating the development of the dependent phenotype. Post-translationally, the GluN2B subunit is phosphorylated subsequent to alcohol exposure (133), particularly in the hippocampus (13), resulting in an increase in receptor function. Over repeated alcohol exposures, an increase in expression of GluN subunits 2A and 2B (134, 135), synaptic-specific clustering of GluNs (136), as well as an increase in GluN-mediated currents (136) are observed (Figure 1B). It is probable that this increase in expression and function of the GluN receptor is a compensatory mechanism against chronic alcohol’s impairment on the receptor; however, when alcohol is absent from the cortical system during withdrawal, the pathologic over-expression of GluNs (137), along with the normalized GABA-ergic function in the absence of alcohol’s facilitating effects, results in cortical hyperactivity and excitotoxicity.
