Animal models for the genetic study of human alcohol phenotypes.

Researchers are increasingly using animal models to study the genetic basis of complex human behaviors, such as alcoholism. The most commonly used animal species are rodents, but other species, such as nonhuman primates, fruit flies, and zebrafish, can also provide important information. A variety of approaches are employed in these studies, particularly knockout and transgenic mice as well as specially bred animal lines that can be used for various genetic analyses, including quantitative trait locus mapping. Other strategies applied in genetic studies in animal models include random mutagenesis, virus-mediated gene transfer, and gene expression profiling. KEY WORDS: genetic theory of AODU (alcohol and other drug use); alcoholic beverage, phenotype; animal model, gene knockout, transgenic technology; QTL (quantitative trait locus) mapping; mutagenesis; gene expression; genetic trait; genetic correlation analysis Vertebrate and invertebrate animal models contribute to researchers' knowledge about the genetics of alcoholism. Overall, the DNA sequences of humans and other organisms (e.g., other primates, rodents, and even fruit flies or yeast) are rather similar (e.g., Bihoreau et al. 2001). Therefore, findings regarding the association of certain genes with specific alcohol-related physiological changes and behaviors (i.e., phenotypes) in animals can at least to some degree be extended to human alcoholics and vice versa. In fact, some researchers have suggested that mouse lines carrying human genes-an approach called gene-swap-will become a common method for studying both the effects of specific genes and genetic differences among humans (Nebert et al. 2000). One example of how genetic discovery in human alcoholics can be translated to animal research involves the dopamine D^sub 2^ receptor gene (called DRD^sub 2^ in humans and Drd^sub 2^ in mice). Dopamine is a brain chemical (i.e., neurotransmitter) used in the communication between nerve cells. To exert its effects, dopamine is released from the signal-emitting cell and binds to docking molecules (i.e., receptors) on the surface of the signal-receiving cell. Several genes encode dopamine receptors, including DRD^sub 2^. More than a decade ago, some studies implicated variations in the DRD^sub 2^ gene as a factor influencing a person's risk of developing severe alcoholism, although subsequent studies have provided mixed support for this claim (e.g., Noble 2000; Matsushita et al. 2001). Subsequently, studies using a technique called quantitative trait locus (QTL) mapping (described in more detail in the section "Specific Genetic Approaches") indicated that a region on mouse chromosome 9, which is similar to a region on human chromosome 11 where the DRD^sub 2^ gene resides, influenced voluntary alcohol consumption in mice (Phillips et al. 1994). Together with the clinical results obtained in humans, this finding led researchers to consider the mouse Drd^sub 2^ gene as a good candidate for further study. Followup work in mice that lacked functional D^sub 2^ receptors (knockout mice, which are also described in the section "Specific Genetic Approaches") provided further evidence of the involvement of this receptor because the knockout mice exhibited markedly reduced alcohol consumption compared with normal litter-mates (Phillips et al. 1998). Researchers also introduced a modified virus into a specific brain region of rats called the nucleus accumbens, which plays an important role in drug reward. The modified virus produced excessive amounts of the D^sub 2^ receptor and resulted in reduced alcohol consumption and preference in the animals (Thanos et al. 2001).1 Although these findings do not prove that the gene identified by QTL mapping on mouse chromosome 9 is Drd^sub 2^, they do provide justification for continued studies of the role of this gene and its product in alcohol consumption. This article describes several of the genetic methods that have been used in various animal models of alcohol research, including rodents and other species. …