Discovering Genes Involved in Alcohol Dependence and Other Alcohol Responses Role of Animal Models: Role of Animal Models

A host of biological (i.e., genetic) and environmental factors interact throughout the addictive process to influence alcohol use and abuse. These processes are accompanied by a number of behavioral and neural events that include, but are not limited to, changes in the motivational effects of ethanol (both rewarding and aversive), tolerance to some effects of ethanol, and withdrawal when ethanol use is discontinued (Koob and Le Moal 2008). The role of genetics in individual differences in the degree and/or the rate of development of all such changes clearly has been illustrated in human genetic studies as well as studies using genetic animal models (for reviews, see Crabbe 2008 and references therein; Heath et al. 2011 and references therein). Although a few genes consistently have demonstrated a role in alcoholism or associated characteristics (i.e., subclinical markers known as endophenotypes) in human studies, their identification has relied heavily on prior knowledge of the physiological responses to alcohol. Thus, these genes primarily encode alcohol-metabolizing enzyme isoforms and neurotransmitter receptor subunits, both of which already had been known to be affected by alcohol (for more information, see the articles by Hurley and Edenberg, pp. 339-344, and by Borghese and Harris, pp. 345-354, in this issue). Moreover, the genetic variants identified to date do not wholly explain the complex genetic susceptibility to alcoholism. Accordingly, researchers need unbiased, systematic approaches to gene discovery in order to discover novel genes and mechanisms and translate them into improved treatment and prevention approaches. One promising approach to achieving this is to conduct genome-wide association studies (GWASs). However, human GWASs require large sample sizes to identify alcoholism susceptibility genes, and the studies published to date have been underpowered and show limited replicability (for a review, see Treutlein and Reitschel 2011 and references therein). The use of preclinical (i.e., animal) models that closely approximate the clinical situation has been essential for elucidating genetic factors involved in the response to alcohol. Although no animal model can exactly duplicate alcoholism in humans, robust animal models for specific alcohol-related traits are useful for identifying potential determinants of liability in humans. These models include, but certainly are not limited to, the following: * Animal models of ethanol self-administration, given that excessive ethanol consumption is a hallmark of alcohol use disorders in humans; * Models of conditioned place preference and conditioned taste aversion to assess the motivational (i.e., rewarding and aversive) effects of ethanol; * Models of ethanol sensitivity, because evidence from human studies indicates that sensitivity to the intoxicating effects of ethanol is a marker of genetic susceptibility to develop alcohol dependence; and * Models of withdrawal, because physiological dependence on alcohol and associated withdrawal symptoms are thought to constitute a motivational force that perpetuates alcohol use and abuse. For recent publications that address potential consilience between human alcohol dependence and animal models in more depth, the reader is referred to Crabbe and colleagues (2010), Ehlers and colleagues (2010), and Sher and colleagues (2010). Studies using robust animal, and particularly mouse, models have been fundamental to unbiased searches for genetic determinants of ethanol responses. For example, researchers have used such models to detect and map quantitative trait loci (QTLs)--chromosomal regions containing or linked to the genes that underlie a quantitative, complex trait. These approaches have identified significant and suggestive QTLs for ethanol sensitivity (e.g., Bennett et al. 2006; Downing et al. 2006; Palmer et al. 2006), consumption (e.g., Belknap and Atkins 2001; Boyle and Gill 2008; Hitzemann et al. …