A persistent high energy status will deplete intracellular [AMP] (Frost et al., 2014), which is essential to activate AMP-activated protein kinase (AMPK), a phylogenetically conserved fuel and energy-sensing enzyme that governs metabolic homeostasis (Hardie et al., 2016). Despite AMPK being a kinase which may likely regulate cellular metabolism via modulating downstream phosphorylation targets, evidence also indicates that AMPK may also control gene expression through metabolites of intermediary metabolism (Sukumaran et al., 2020). AMPK activity enhances the expression of one or more glucose transporters (GLUT1, GLUT3 and GLUT4) commonly found in the brain (Handa et al., 2000), so we speculate that diminished AMPK could reduce glucose availability (Fig. 1D), as seen in other tissues (Habegger et al., 2012). This interrupted energy supply may lead to changes in neuronal function (Volkow et al., 2015, Volkow et al., 2017), likely including excitability, and account for changes in behaviour associated with alcohol intake.
