Titrating Tipsy Targets: The Neurobiology of Low-Dose Alcohol

Abstract

Limited attention has been given to our understanding of how the brain responds to low-dose alcohol (ethanol) and what molecular and cellular targets mediate these effects. Even at concentrations lower than 10mM (0.046 g% blood alcohol concentration, BAC), below the legal driving limit in the USA (BAC 0.08 g%), alcohol impacts brain function and behavior. Understanding what molecular and cellular targets mediate the initial effects of alcohol and subsequent neuroplasticity could provide a better understanding of vulnerability or resilience to developing alcohol use disorders. We review here what is known about the neurobiology of low-dose alcohol, provide insights into potential molecular targets, and discuss future directions and challenges in further defining targets of low-dose alcohol at the molecular, cellular, and circuitry levels.

Keywords: alcohol; ethanol; intoxication; low-dose; molecular targets; neurobiology.

Figure 1

Effects of alcohol (ethanol) related to blood alcohol levels. Alcohol has a biphasic dose-effect curve in humans. At lower concentrations, such as at 0.05 g% (10.9 mM) and below, alcohol causes disinhibition and relaxation. At higher concentrations, alcohol impairs motor function (at 0.1 – 0.2 g% or 22 – 44 mM) and causes stupor (at 0.2 – 0.3 g% or 44 – 65 mM), coma (at 0.3 – 0.4 g% or 65 – 87 mM), and even death (at 0.4 – 0.5 g% or 87 mM – 109 mM). The legal limit of blood alcohol concentration (BAC) for driving in the USA is 0.08 g% corresponding to 17.4 mM.

Figure 2

Sensitivity of Molecular Targets to Alcohol at Concentrations ≤10 mM. Activity changes of multiple receptors, channels, and signaling molecules responding to alcohol at concentrations ≤10 mM. The graph provides an overview of sensitivities of different molecular targets to alcohol based on data from expression systems and isolated neurons and is not intended to demonstrate strict comparisons. References to the data are listed in Table 1. Abbreviations: BK, large-conductance calcium-gated potassium channel; HEK, human embryonic kidney cell line; Hipp, hippocampus; NAc, nucleus accumbens; Neurohyp., neurohypophysis; 3T3, mouse fibroblast 3T3 cell line (for other targets see text).

Figure 3

Putative Alcohol Binding Sites Identified in Diverse Molecular Targets of Alcohol. (A) Alcohol (orange and red spheres) in the inter-subunit cavity shown in the crystal structure of an alcohol sensitized GLIC F14’A mutant co-crystallized with alcohol [55]. (B) Alcohol modulation sites of pentameric ligand-gated ion channels, including the GABAA, glycine (Gly), and nicotinic acetylcholine (ACh) receptor subtypes, mapped onto the crystal structure of two neighboring subunits of the prokaryotic GLIC protein (depicted by ribbons). Putative binding sites are indicated by colored ribbons. Residues implicated in the interactions of alcohol with multiple subtypes of GABA_A, glycine (Gly), and nicotinic acetylcholine (ACh) receptors, are labeled by notation [56]. (C) Molecular model of the alcohol site in the NMDA receptor formed by the transmembrane (TM)3 domain of the GluN1 subunit (grey) and the TM4 domain of GluN2B subunit (blue). The labeled residues in intersubunit interfaces of the TM3 and TM4 domain interact to regulate alcohol action [46]. (D) Discrete alcohol sensing regions in the cytosolic tail domain (CTD) of the BK channel depicted using the mSlo1 CTD homology model based on the crystal structure of hSlo1. The hydrogen bond between alcohol and K361 is shown as a dotted line in the region 2 [74]. (E) Potential alcohol binding sites in L1 adhesion molecules identified by photo-labeling with azilalcohol. Potential alcohol binding pocket (E33 and Y418) and a disease causing residue (L120) are mapped onto horseshoe-shaped immunoglobulin (lg)1-4 domains of human L1 structure modeled based on the crystal structure of axonin Ig1–4 [77].