Academic journal article Alcohol Research

Applications of Transgenic and Knockout Mice in Alcohol Research

Academic journal article Alcohol Research

Applications of Transgenic and Knockout Mice in Alcohol Research

Article excerpt

Multiple genetic and environmental factors contribute to the development of alcoholism. Researchers attempting to elucidate the roles of specific genes in alcoholism risk have benefited from advances in genetic engineering. Two important tools used by researchers include transgenic mice, in which a foreign gene is integrated into an animal's genetic material, and knockout/knock-in mice, in which targeted genes either are rendered nonfunctional or are altered. Both of these animal models are currently used in alcohol research to determine how genes may influence the development of alcoholism in humans. KEY WORDS: animal model; transgenic technology; gene knockout technology; gene expression; DNA; neurotransmitters; GABA receptors; stem cell; receptor proteins; protein kinases

Alcoholism is a complex disorder that encompasses several physiological and behavioral characteristics (also referred to as phenotypes), including atypical responses to alcohol in initial sensitivity, tolerance, consumption, and withdrawal as well as vulnerability to the rewarding effects of alcohol. Human and animal studies have both shown that these aspects of alcoholism are often mediated by chemical pathways in the brain, known as neurotransmitter systems (Diamond and Gordon 1997; Harris 1999). A major goal for neuroscientists has been to identify genes and proteins in the brain that influence the expression of alcoholism. Increased knowledge of chemicals in the brain and receptor proteins (i.e., protein molecules that recognize and bind neurotransmitters) has provided scientists with a priori reasons for studying specific genes and proteins, which are sometimes referred to as candidate genes and proteins. For example, alcohol affects nearly all brain activity, including enhancement of inhibition, mediate d by the gamma-aminobutyric acid (GABA) neurotransmitter system; activation of reward pathways that are dopaminergic (DA) and serotonergic (5-HT); and effects on enzyme proteins that are located inside nerve cells (i.e., neurons) (Diamond and Gordon 1997; Grobin et al. 1998). Therefore, these systems (as well as several others, including nonneuronal genes) have produced many candidate genes to investigate for their roles in the development of alcoholism.

One approach that is particularly effective in the hunt for candidate genes is the reverse genetics approach, in which a gene of interest is altered to change its expression, or function, in the entire animal. This approach involves generating transgenic mice, in which a foreign gene is integrated into an animal's genetic material, as well as knockout or knock-in mice, in which candidate genes are either inactivated or altered, resulting in a lack of or change in protein expression. Although mouse models may seem poor research tools for studying the genetics of human neurophysiology and behavior, substantial genetic similarities exist between mice and humans, and known correspondence exists between mouse chromosomal regions and human chromosomes (Silver 1995).

This article describes the generation of transgenic mice and knockout/knock-in mice and recent examples of how these techniques have been applied in alcohol research.

TRANSGENICS

In the context of mouse models, the term transgenic refers to the introduction of a foreign [1] gene (known as a transgene) into the genetic material of a mouse in both the reproductive (i.e., germ) cells and the nonreproductive (i.e., somatic) cells. This process leads to the expression and propagation of the gene across future generations. Often the purpose of this technique is to create mice that express more than normal amounts of the gene product (i.e., protein). In some applications, however, the scientific goal is to introduce a different form of the gene in question. This technique allows researchers to evaluate the role of specific genes in the development of disease. For example, a line of transgenic mice generated to study alcoholism would carry a gene that is known or suspected to have a role in some aspect of the disease. …

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