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Review
. 2017 Jan;16(1):139-148.
doi: 10.1111/gbb.12363.

Alcohol-dependent molecular adaptations of the NMDA receptor system

N Morisot  1 , D Ron  1
Affiliations
Review

Alcohol-dependent molecular adaptations of the NMDA receptor system

N Morisot et al. Genes Brain Behav. 2017 Jan.

Abstract

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.

Keywords: AMPA; Addiction; CaMKII; Fyn; NMDA; PTPalpha; STEP; alcohol; amygdala; kinase; mTOR; nucleus accumbens; phosphatase; signaling; striatum.

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Figures

Figure 1
Figure 1. Moderate consumption of alcohol does not trigger Fyn activation in the DMS
Mice had CA10% (black) or water only (white) in a 2BC paradigm for 21 days, and the DMS was dissected immediately after the last 24-h alcohol drinking session. (a) pY417/420[Fyn/Src] as well as the total protein level of Fyn and actin, which was used as a loading control, were measured by western blot analysis. (b) Histogram shows the mean ratio of pY417/420[Fyn/Src] to total Fyn ± SEM, expressed as percentage of water controls. Data analysis indicates that CA10% does not affect Fyn activation in the DMS (t10 = 0.92, P = 0.38, unpaired Student's t-test). n = 6.
Figure 2
Figure 2. Molecular pathways transducing alcohol's signal in the DMS
Alcohol activates PKA, which phosphorylates STEP inhibiting the activity of the phosphatase. Inhibition of STEP allows for the long-lasting activation of Fyn. Alcohol also enables the membranal colocalization of Fyn with its activator PTPalpha. Active Fyn phosphorylates GluN2B, which enhances the activity of the channel. Calcium entry through the GluN2B-containing NMDARs enables the activation of CaMKII. CaMKII activation promotes the forward trafficking of the AMPAR subunits, which in turn contributes to synaptic plasticity and alcohol dependent behavioral phenotypes.
Figure 3
Figure 3. Molecular pathways transducing alcohol's signal in the NAc
Alcohol inhibits the activity of the NMDARs, which may contribute to the activation of mTORC1. mTORC1 phosphorylates its downstream substrates 4-eukaryote binding protein (4-EBP) and the ribosomal protein S6 kinase (S6K) resulting in the induction of the translational machinery and in the translation of the microtubule-binding protein (CRMP-2), the scaffolding proteins HOMER and PSD-95 as well as the GluA1 subunit of AMPAR, all of which play a major role in synaptic plasticity and alcohol-related phenotypes.
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