Acute ethanol treatment increases Fyn activity in the rat dorsal striatum,267 cerebral cortex, and cerebellum.268 Ethanol also acutely and transiently inhibits NMDA receptor-mediated excitatory postsynaptic potentials (EPSPs) in the hippocampus, which eventually return to baseline, indicating that NMDA receptors develop an acute tolerance to the inhibitory effects of ethanol.269 Fyn is critical for this process since Fyn knockout mice do not show acute tolerance to ethanol.269 Fyn and NMDA NR2B are found in a complex with the scaffolding protein RACK1,267,270,271 and RACK1 inhibits phosphorylation of NR2B by Fyn.270 Ethanol increases NMDA NR2B subunit phosphorylation267,269 by dissociating this complex, enabling Fyn to phosphorylate NR2B and increase NMDA receptor function.271 Overexpression of RACK1 prevents phosphorylation of NR2B by Fyn and prevents the development of tolerance to the inhibitory effects of ethanol on NMDA receptor function in vitro.271 Thus, ethanol itself normalizes NMDA function by stimulating RACK1 dissociation from the complex, thereby enabling Fyn to phosphorylate NR2B and increase NMDA receptor function.
