Letter: Inherited differences in intensity of alcohol withdrawal reactions in mice.
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Biomedical subjects
Publications and source records attributed to D B Goldstein.
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Intoxicating blood levels of ethanol are maintained for several days in mice housed in an atmosphere of ethanol vapor. On removal from the alcohol, all the mice develop withdrawal signs. The signs can be graded to indicate the time course and intensity of the withdrawal reaction.
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The homeostat hypothesis of drug addiction states that tolerance and physical dependence may both represent adaptive processes, the body's responses to drugs that change the internal milieu. This conceptual framework inextricably links physical dependence with functional tolerance. Dependence may arise by multiple mechanisms, so that different signs, such as body temperature or CNS excitability, may show different degrees of dependence or may have different time courses. Tolerance may be similarly diverse. It is difficult to test whether tolerance and dependence have the same time course because it is hard to find exactly equivalent signs for such a test. The discrepant data from different laboratories on the rate of recovery from physical dependence may be due to the use of different withdrawal signs as indices. Dissociation of tolerance and dependence has been reported in mice treated with 6-hydroxydopamine, where dependence develops without evidence of tolerance. Conversely, tolerance without expression of dependence is seen in experiments on membranes and synapses in vitro. Changes in lipid composition of cell membranes may explain some kinds of tolerance.
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Our understanding of the structure and function of biomembranes is now at a stage where we can begin to examine drug actions on the membrane bilayer. Cells need a certain optimal degree of fluidity in their membranes and some organisms can adapt their membrane composition to maintain the appropriate fluidity under changing environmental conditions. Chronic administration of membrane-disrupting drugs may evoke such an adaptive process, which would show itself in vivo as drug tolerance.