Alcohol Dependence and Withdrawal: A Genetic Animal Model

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Abstract
Using the techniques of selective breeding, mouse lines have been developed that express severe (Withdrawal Seizure Prone: WSP) or mild (Withdrawal Seizure Resistant: WSR) handling induced convulsions after cessation of chronic ethanol exposure. These lines differ at least ten-fold in severity of withdrawal after identical ethanol treatment. One feature of the genetic model is that other traits which distinguish these lines are presumably influenced by those genes determining ethanol withdrawal severity. WSP and WSR mice do not differ markedly in the metabolism of ethanol. In addition to handling induced convulsions, they also differ in other withdrawal signs: for example, WSP mice show more pronounced tremor. WSP and WSR mice do not differ in sensitivity to ethanol's hypothermic, anesthetic, or locomotor stimulant effects, nor in the magnitude of tolerance development to these responses. This suggests that sensitivity, tolerance and dependence are distinct genetic entities. WSP mice also display more severe withdrawal from diazepam, phenobarbital, and nitrous oxide than WSR mice, suggesting that some genes generally predispose mice to withdrawal from depressants. WSP mice display withdrawal handling induced convulsions after a single dose of ethanol, pentobarbital, or diazepam. The effective dose for producing drug seizures is not markedly different between WSP and WSR mice for a number of compounds with varied mechanisms of action. However, WSP mice are more sensitive than WSR mice to the effects of acute doses of convulsants to elevate handling induced convulsions. WSP mice have more binding sites in hippocampus for the N-methyl-D-aspartate antagonist MK 801. Binding of this ligand is increased during ethanol dependence in both mouse lines. N-methyl-D-aspartate is the only drug tested which did not elevate handling induced convulsions in either mouse line. However, when given during withdrawal from a single ethanol injection, WSP but not WSR mice showed increased handling induced convulsions. Both WSP and WSR mice showed increased handling induced convulsions when given pentylenetetrazole during acute ethanol withdrawal. WSP and WSR mice were found to develop kindled seizures upon repeated administration of pentylenetetrazole, but they kindled at the same rate. WSP mice have been found to have a 70 % deficiency of zinc in hippocampal mossy fibers. While control WSP mice have only slightly fewer dihydropyridine-sensitive calcium channel binding sites than WSR in whole brain homogenates, after chronic ethanol administration WSP mice showed marked increases in these sites compared to WSR. The relationships among these differences are currently under investigation at the behavioral and biochemical levels.