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Neurochemical Mechanisms Underlying Alcohol Withdrawal

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Neurochemical Mechanisms Underlying Alcohol Withdrawal Neurochemical Mechanisms Underlying Alcohol Withdrawal John Littleton, MD, Ph.D. 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 uring the past 25 years research- science models used to study with- of the reasons why advances in basic ers have made rapid progress drawal neurochemistry as well as a research have not yet been translated Din understanding the chemi- reluctance on the part of clinicians to into therapeutic gains and suggests cal activities that occur in the nervous consider new treatments. No reason areas for future improvement. system (i.e., the neurochemistry) during exists to criticize either scientists or alcohol withdrawal (AW), primarily clinicians for this situation; from the from experiments using animal models basic science viewpoint, it was necessary Neurochemical Concepts of alcohol dependence (Samson and to understand the neurochemical of Physiological Dependence Harris 1992). At the same time, advances processes in relatively simple models have been made in the clinical treat- first, and from the clinicians’ viewpoint, It has been said that Darwin’s theory ment of AW, making detoxification it made no sense to change withdrawal of natural selection is the “single best a routine procedure that no longer is treatments (e.g., the use of benzodi- idea” in biology. A candidate for a life-threatening (Romach and Sellers azepines) that had proven successful. similar tribute in drug-dependence 1991). For the most part, however, Now may be the right time to research is the suggestion made by these treatment advances have evolved rethink our goals for both research independently from the developments and treatment of AW, however. This in neurochemical understanding. The article reviews current concepts and JOHN LITTLETON, MD, PH.D., reasons for this independence are com- developments in basic research on the is a professor in the Department of plex, and they include the limited neurochemical mechanisms underlying Pharmacology, University of Kentucky, clinical relevance of some of the basic AW. The article also considers some Lexington, Kentucky. Vol. 22, No. 1, 1998 13 C.K. Himmelsbach more than 50 years seesaw (see figure 1). The brain is in same: an adaptive neurochemical ago regarding the relation of toler- a balanced state before alcohol expo- response designed to oppose alcohol’s ance, dependence, and withdrawal sure. When a person consumes acute neurochemical effects. It should (Himmelsbach 1941). Based on his alcohol, its acute effect (which often be emphasized, however, that some observations of morphine-dependent is the effect the person is seeking) is to other types of tolerance mechanisms patients, Himmelsbach suggested that unbalance the neurochemical equilib- can develop without necessarily causing physiological mechanisms which rium of the brain, thereby tilting the a withdrawal syndrome and, as dis- maintain a stable state of equilibrium seesaw. If the alcohol exposure contin- cussed later, this simple scheme does (i.e., homeostasis) in the patient’s ues, the brain institutes an opposing not take into account what may hap- body and brain are responsible for adaptation (i.e., neuroadaptation) to pen after repeated episodes of alcohol drug tolerance, but absence of the balance the effect of the alcohol and administration and withdrawal. drug exposes these same homeostatic restore neurochemical equilibrium. In Himmelsbach’s idea has provided a mechanisms and leads to the with- other words, the brain develops toler- much-needed framework for investiga- drawal syndrome. Clinically, this ance for the drug. However, the brain tions of the neurochemical adaptations theory provides the framework for the is also in a state of physiological depend- that occur in alcohol dependence and modern category of “physiological ence at this point: When alcohol expo- the way in which these adaptations dependence” and its current diagnos- sure ceases, the new neuroadaptation may precipitate withdrawal. Although tic criteria—the presence of tolerance now unbalances the brain’s neuro- the adoption of this framework has and/or a specific withdrawal syndrome chemistry. And, like tilting the seesaw been largely beneficial, it also has (American Psychological Association to the opposite side, the unbalanced been restrictive in many ways, not 1994). Himmelsbach’s concept has adaptation produces a functional least because it has been interpreted dominated almost all neurochemical effect on the brain (i.e., the with- to imply that all the elements involved explanations for withdrawal from drawal syndrome) that is opposite in tolerance, dependence, and with- alcohol and other drugs since it was from the effects originally produced drawal should be found within a first proposed. by alcohol. Thus, in Himmelsbach’s single neurochemical system. For At the neurochemical level, Him- scheme, the cause of both tolerance example, if alcohol is found to inhibit melsbach’s idea can be expressed as a and the withdrawal syndrome is the (i.e., reduce the activity of) a particu- Administration of alcohol Alcohol-free Acute state alcohol Alcohol effect 1 CNS Opposing equilibrium neuroadaptation Adaptation Alcohol Adaptation Recovery from Alcohol neuroadaptation tolerance Withdrawal Removal syndrome of alcohol Figure 1 Pictorial representation of the Himmelsbach hypothesis as it applies to alcohol use. The balanced seesaw on the upper left side of the cycle represents brain neurochemistry in an alcohol-free state (i.e., before the brain has been exposed to alcohol). Consuming alcohol initially unbalances brain chemistry to produce the acute effects associated with alcohol use (e.g., sedation and incoordination). The brain then responds to this disruption by inducing an opposing chemical adaptation that tends to restore the neurochemical balance. At this stage, the effects of a given dose of alcohol are diminished (i.e., tolerance exists). If alcohol is removed, the adaptation is exposed, unbalancing the brain’s neurochemistry in the opposite direction. The result is a withdrawal syndrome that includes signs and symptoms (e.g., agitation and seizures) that are opposite to alcohol’s initial effects. These disturbances will continue until the adaptation can be removed from the brain (or until alcohol is consumed again), restoring equilibrium. 1 CNS = central nevous system. 14 Alcohol Health & Research World Neurochemical Mechanisms Underlying Alcohol Withdrawal lar chemical messenger (i.e., neuro- several ways. Short-term chemical Animal Models of Alcohol transmitter1) system in the brain, then modifications of receptor proteins on Withdrawal the subsequent adaptation is predicted the target neurons2 can increase (or to increase activity in the same neuro- decrease) the neurotransmitter’s Meaningful research on neuroadapta- transmitter system. This increase in effects. To use an example from another tion underlying AW became possible neurochemical activity should coun- drug of dependence, the immediate only in the early 1970’s, when investiga- terbalance alcohol’s effects, causing effects of nicotine on nerves are limited tors developed models of physiological tolerance when alcohol is still present because “nicotinic” receptors for the dependence and withdrawal in labora- and a withdrawal syndrome when it transmitter acetylcholine become tory animals (for example, see Goldstein is removed. An alteration of this type desensitized (both to nicotine and and Pal 1971). Before this development, (i.e., within the same system) is acetylcholine). Desensitization of most preclinical research focused on referred to as a “homologous” adapta- those receptor proteins is caused by the alcohol “preference” of laboratory tion. One of the complexities of the short-lived modifications in their rodents that consumed alcohol volun- human brain, however, is that an structure. Alternatively, for longer tarily. Because of the limited intake effect on one transmitter system may term changes, the system may increase of alcohol by most rodents and the be counterbalanced by an adaptation or decrease the number of receptor rapid elimination of alcohol
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