Alcohol-dependent molecular adaptations of the NMDA receptor system

Phenotypes such as motivation to consume alcohol, goal-directed alcohol seeking and habit formation take part in mechanisms underlying heavy alcohol use. Learning and memory processes greatly contribute to the establishment and maintenance of these behavioral phenotypes. The N-methyl-d-aspartate receptor (NMDAR) is a driving force of synaptic plasticity, a key cellular hallmark of learning and memory. Here, we describe data in rodents and humans linking signaling molecules that center around the NMDARs, and behaviors associated with the development and/or maintenance of alcohol use disorder (AUD). Specifically, we show that enzymes that participate in the regulation of NMDAR function including Fyn kinase as well as signaling cascades downstream of NMDAR including calcium/calmodulin-dependent protein kinase II (CamKII), the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and the mammalian target of rapamycin complex 1 (mTORC1) play a major role in mechanisms underlying alcohol drinking behaviors. Finally, we emphasize the brain region specificity of alcohol's actions on the above-mentioned signaling pathways and attempt to bridge the gap between the molecular signaling that drive learning and memory processes and alcohol-dependent behavioral phenotypes. Finally, we present data to suggest that genes related to NMDAR signaling may be AUD risk factors.