N-Methyl-d-aspartate receptors (NMDARs) are major targets of both acute and 
chronic alcohol, as well as regulators of plasticity in a number of brain 
regions. Aberrant plasticity may contribute to the treatment resistance and high 
relapse rates observed in alcoholics. Recent work suggests that chronic alcohol 
treatment preferentially modulates both the expression and subcellular 
localization of NMDARs containing the GluN2B subunit. Signaling through synaptic 
and extrasynaptic GluN2B-NMDARs has already been implicated in the 
pathophysiology of various other neurological disorders. NMDARs interact with a 
large number of proteins at the glutamate synapse, and a better understanding of 
how alcohol modulates this proteome is needed. We employed a discovery-based 
proteomic approach in subcellular fractions of hippocampal tissue from chronic 
intermittent alcohol (CIE)-exposed C57Bl/6J mice to gain insight into 
alcohol-induced changes in GluN2B signaling complexes. Protein enrichment 
analyses revealed changes in the association of post-synaptic proteins, 
including scaffolding, glutamate receptor and PDZ-domain binding proteins with 
GluN2B. In particular, GluN2B interaction with metabotropic glutamate (mGlu)1/5 
receptor-dependent long-term depression (LTD)-associated proteins such as Arc 
and Homer 1 was increased, while GluA2 was decreased. Accordingly, we found a 
lack of mGlu1/5 -induced LTD while α1 -adrenergic receptor-induced LTD remained 
intact in hippocampal CA1 following CIE. These data suggest that CIE 
specifically disrupts mGlu1/5 -LTD, representing a possible connection between 
NMDAR and mGlu receptor signaling. These studies not only demonstrate a new way 
in which alcohol can modulate plasticity in the hippocampus but also emphasize 
the utility of this discovery-based proteomic approach to generate new 
hypotheses regarding alcohol-related mechanisms.