Academic journal article Genetics

A Novel Cholinergic Action of Alcohol and the Development of Tolerance to That Effect in Caenorhabditis Elegans

Academic journal article Genetics

A Novel Cholinergic Action of Alcohol and the Development of Tolerance to That Effect in Caenorhabditis Elegans

Article excerpt

THE abuse of alcohol is a cause of significant societal and health-related problems. Despite the common usage of this drug, the molecular underpinnings of alcohol's acute actions on the brain are poorly understood. Alcohol (ethanol) has biphasic behavioral effects in humans and other animals, acting as a stimulant at lower concentrations and as a depressant at higher concentrations. Understanding the molecular nature of these biphasic effects is made difficult by the fact that ethanol interacts with, and alters the function of, many proteins, including neurotransmitter receptors and ion channels (Harris et al. 2008; Spanagel 2009). A commonly suggested class of ethanol targets is ligand-gated ion channels (LGICs), which include NMDA glutamate receptors, and members of a sub-class of LGICs, the Cys-loop superfamily, including GABAa, glycine, and nicotinic acetylcholine receptors (nAChRs) (Olsen et al. 2014). Effects on the GABAa and glutamate receptors are hypothesized to play a significant role in the depressant effects of ethanol (Harris et al. 2008). Locomotor activation by low to moderate concentrations of ethanol in rodents is thought to model the euphoric effects of ethanol in humans (Phillips and Shen 1996). Locomotor activation by ethanol has been linked to increased dopamine release in neural reward pathways, possibly via mechanisms that involve inhibition of the inhibitory GA-BAb metabotropic receptors by ethanol (Holstein et al. 2009; Kruse et al. 2012) and/or by ethanol activation of neuronal nAChRs (Soderpalm et al. 2000; Larsson et al. 2002; Kamens and Phillips 2008; Kamens et al. 2009).

Individual variation that alters the mechanisms responsible for the acute behavioral effects of ethanol is likely to contribute to variation in predisposition to develop alcohol use disorders (AUDs). An individual's level of response (LR) to acute ethanol intoxication is determined by two major opposing biological forces, the degree of sensitivity to intoxication and the rate at which tolerance develops to that acute intoxication during the intoxication session (called acute functional tolerance) (Newlin and Thomson 1990). LR has genetic determinants (Kalu et al. 2012) and LR in naive drinkers is a predictor of the predisposition to develop AUDs later in life (Schuckit 1994; Volavka et al. 1996; Heath et al. 1999). Therefore, it is important that we better understand the pathways responsible for the behavioral actions of ethanol and the mechanisms by which acute functional tolerance can develop to those behavioral effects. Studies in selectively bred mouse strains suggest that ethanol-induced locomotor activation and the rate of development of acute functional tolerance may share common mechanisms (Ponomarev and Crabbe 2002).

Caenorhabditis elegans represents a powerful model for identifying drug targets, using genetic approaches (Van Swinderen et al. 1999; Davies et al. 2003; Artal-Sanz et al. 2006; Kaletta and Hengartner 2006; Kwok et al. 2006). C. elegans are sensitive to acute ethanol exposure, demonstrating an increased speed of locomotion at low ethanol concentrations (Graham et al. 2009) and decreased amplitude of body bends and decreased rates of crawling, swimming, egg laying, and pharyngeal pumping at higher concentrations of ethanol (Davies et al. 2003; Mitchell et al. 2007; Speca et al. 2010). Ethanol also produces disinhibition of certain crawling behaviors that would normally be inhibited in a liquid environment (Topper et al. 2014). Acute functional tolerance, which is unrelated to metabolism of the drug, develops rapidly to the effects of ethanol on the speed of locomotion (Davies et al. 2004; Alaimo et al. 2012; Bettinger et al. 2012; Raabe et al. 2014). Longer ethanol exposures followed by removal from the drug can lead to withdrawal-related phenotypes (Davies et al. 2004; Mitchell et al. 2010). Therefore, these drug-induced behavioral effects are indicative of ethanol having activating and depressing actions in C. …

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