Neurochemical Mechanisms Underlying Alcohol Withdrawal

More than 50 years ago, C.K. Himmelsbach first suggested that physiological mechanisms responsible for maintaining a stable state of equilibrium (i.e., homeostasis) in the patient's body and brain are responsible for drug tolerance and the drug withdrawal syndrome. In the latter case, he suggested that the absence of the drug leaves these same homeostatic mechanisms exposed, leading to the withdrawal syndrome. This theory provides the framework for a majority of neurochemical investigations of the adaptations that occur in alcohol dependence and how these adaptations may precipitate withdrawal. This article examines the Himmelsbach theory and its application to alcohol withdrawal; reviews the animal models being used to study withdrawal; and looks at the postulated neuroadaptations in three systems-the gamma-aminobutyric acid (GABA) neurotransmitter system, the glutamate neurotransmitter system, and the calcium channel system that regulates various processes inside neurons. The role of these neuroadaptations in withdrawal and the clinical implications of this research also are considered. KEY WORDS: AOD withdrawal syndrome; neurochemistry; biochemical mechanism; AOD tolerance; brain; homeostasis; biological AOD dependence; biological AOD use; disorder theory; biological adaptation; animal model; GABA receptors; glutamate receptors; calcium channel; proteins; detoxification; brain damage; disease severity; AODD (alcohol and other drug dependence) relapse; literature review During the past 25 years researchers have made rapid progress in understanding the chemical activities that occur in the nervous system (i.e., the neurochemistry) during alcohol withdrawal (AW), primarily from experiments using animal models of alcohol dependence (Samson and Harris 1992). At the same time, advances have been made in the clinical treatment of AW, making detoxification a routine procedure that no longer is life-threatening (Romach and Sellers 1991). For the most part, however, these treatment advances have evolved independently from the developments in neurochemical understanding. The reasons for this independence are complex, and they include the limited clinical relevance of some of the basic science models used to study withdrawal neurochemistry as well as a reluctance on the part of clinicians to consider new treatments. No reason exists to criticize either scientists or clinicians for this situation; from the basic science viewpoint, it was necessary to understand the neurochemical processes in relatively simple models first, and from the clinicians' viewpoint, it made no sense to change withdrawal treatments (e.g., the use of benzodiazepines) that had proven successful. Now may be the right time to rethink our goals for both research and treatment of AW, however. This article reviews current concepts and developments in basic research on the neurochemical mechanisms underlying AW. The article also considers some of the reasons why advances in basic research have not yet been translated into therapeutic gains and suggests areas for future improvement. NEUROCHEMICAL CONCEPTS OF PHYSIOLOGICAL DEPENDENCE It has been said that Darwin's theory of natural selection is the "single best idea" in biology. A candidate for a similar tribute in drug-dependence research is the suggestion made by C.K. Himmelsbach more than 50 years ago regarding the relation of tolerance, dependence, and withdrawal (Himmelsbach 1941). Based on his observations of morphine-dependent patients, Himmelsbach suggested that physiological mechanisms which maintain a stable state of equilibrium (i.e., homeostasis) in the patient's body and brain are responsible for drug tolerance, but absence of the drug exposes these same homeostatic mechanisms and leads to the withdrawal syndrome. Clinically, this theory provides the framework for the modern category of "physiological dependence" and its current diagnostic criteria-the presence of tolerance and/or a specific withdrawal syndrome (American Psychological Association 1994). …