FIGURE 1.

Alcohol affects local translation of proteins in amygdala of alcohol-dependent rats. Alcohol exposure using conditioning chambers, as well as a non-pharmacologically active alcohol injection (priming) that served as an odor-taste cue, increased mTORC1 (mammalian target of rapamycin complex 1) activation and the phosphorylation/activation of its downstream substrates, such as eukaryotic translation initiation factor-4E binding protein (4E-BP), S6 kinase (S6K) and the S6K substrates, and increased expression of post-synaptic density-95 (PSD95) and the AMPA receptor GluA1 subunit (Barak et al., 2013). These effects were abolished by the mTORC1 inhibitor, rapamycin. A second pathway by which alcohol mediates synaptic translation is by increasing extracellular glutamate. This leads to activation of voltage-dependent Ca²⁺ channels (VDCCs) and activity-dependent release of brain-derived neurotrophic factor (BDNF). BDNF then binds and stimulates its receptor, tropomyosin-related kinase B (TrkB), activating downstream signaling pathways, including phosphatidyl inositol-3 kinase (PI3K), Akt and Ras, stimulating mTORC1, which culminates in the signaling effects described above. The increased GluA1-subunits are inserted into the membrane, increasing excitation and alcohol-sensitive substrates. Thus, mTORC1 activation mediates the translation of specific synaptic proteins that are important in plasticity processes. Figure and legend were adapted from Duman and Voleti (2012). Abbreviations: 4E-BP, 4E binding protein; eEF2K, eukaryotic elongation factor-2 kinase; ERK, extracellular signal-regulated kinase; MEK, MAP/ERK kinase; P indicates phosphorylated protein.