HISTORICAL BACKGROUND The use of genetic animal models in neuroscience and biomedical research is showing dramatic growth. The earliest application of these models to research on drug mechanisms was in the area of alcohol research. Mardones (1951) reported successful selective breeding of rats preferring and not preferring to drink alcohol under various conditions of dietary deficiency, suggesting genetic control of alcohol drinking. McClearn and Rodgers (1959, 1961) described differences among inbred mouse strains in preference for 10Ofo ethanol solutions versus tap water. Active exploration of this phenomenon continued until the early 1970s, eventually spawning the entire range of alcohol genetic research reviewed in Chapters 2 and 3 of this volume. Notably, oral alcohol self-administration has served as the basis for the development of several rat lines bred for preference or aversion, and these lines are very actively being investigated. The pioneering research of Dr. McClearn and others was very wide ranging in its conceptual scope and at least touched on all issues currently under intense investigation. The basic approach was to identify high and low preferrers among inbred strains of mice and to search for preference correlates in other traits. One major thrust of early research was to attempt to explain strain differences in preference as a function of underlying differences in patterns of caloric utilization. Reviews of these studies concluded that nutritional factors could not completely explain preference differences (Rod gers, 1966; McClearn, 1968)."

HISTORICAL BACKGROUND The use of genetic animal models in neuroscience and biomedical research is showing dramatic growth. The earliest application of these models to research on drug mechanisms was in the area of alcohol research. Mardones (1951) reported successful selective breeding of rats preferring and not preferring to drink alcohol under various conditions of dietary deficiency, suggesting genetic control of alcohol drinking. McClearn and Rodgers (1959, 1961) described differences among inbred mouse strains in preference for 10Ofo ethanol solutions versus tap water. Active exploration of this phenomenon continued until the early 1970s, eventually spawning the entire range of alcohol genetic research reviewed in Chapters 2 and 3 of this volume. Notably, oral alcohol self-administration has served as the basis for the development of several rat lines bred for preference or aversion, and these lines are very actively being investigated. The pioneering research of Dr. McClearn and others was very wide ranging in its conceptual scope and at least touched on all issues currently under intense investigation. The basic approach was to identify high and low preferrers among inbred strains of mice and to search for preference correlates in other traits. One major thrust of early research was to attempt to explain strain differences in preference as a function of underlying differences in patterns of caloric utilization. Reviews of these studies concluded that nutritional factors could not completely explain preference differences (Rod gers, 1966; McClearn, 1968)."

Found in all organisms, the alpha-keto acid dehydrogenase complexes have central roles in cellular metabolism and are major sites of regulation. The understanding of the organization, function and regulation of these quintessential multienzyme complexes has been greatly advanced by studies employing molecular biology and biophysical techniques. Although these enzyme systems have some features in common, their diversity in fulfilling unique organism - or tissue - specific roles is truly amazing. These systems have medical importance in areas ranging from defects in regulation (linked to diabetes, heart disease, obesity, nutrition defects), to inherited diseases (inborn errors, maple syrup urine disease) to acquired immune diseases (primary biliary cirrhosis). This book brings together wide-ranging recent findings on the structure(function relationships, gene regulation, and genetic defects of the alpha-keto acid dehydrogenase complexes, namely the pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and the branched-chain alpha-keto acid dehydrogenase complexes. A wide variety of experimental approaches together with new results presented in this book should serve as a resource for beginning to established investigators in the field as well as scientists who are interested in mitochondria, dehydrogenases, kinases, phosphatases, lipoic acid, thiamine pyrophosphate, and enzyme complexes.