Central to understanding the etiology of alcoholism is the issue of how the post-absorptive effects of ethanol may influence drinking. In the proposed studies C57BL/6J mice will be used to evaluate the interaction between blood alcohol and voluntary alcohol consumption. Since C57 mice are not alcoholic the ultimate connection with human alcoholism is based on the assumption that the best way animal studies can make a contribution is: to provide a clear understanding of the physiological determinants of normal alcohol intake; to clarify the distinction between nutritional and alcoholic drinking; and to be prepared to follow leads which suggest alcoholic drinking when they arise (e.g., Experiment B4). Computer techniques which monitor ad libitum drinking and make minute-to-minute estimates of the plasma ethanol concentrations will be used: (1) to monitor the effect of i.p. vs orally administered ethanol on subsequent drinking; (2) to evaluate whether spontaneous drinking produces brief episodes of intoxication; (3) to calculate the probability of ethanol intake as a function of the plasma concentration; (4) to compare the effects of blood alcohol vs nutritional satiety in limiting the intake of ethanol; and (5) to determine how mice can accommodate a large increase in drinking when the ethanol solution is sweetened with sugar. To determine why C57 mice treated with the alcohol dehydrogenase inhibitor, 4-Methylpyrazole (4MP) continue to select ethanol in preference to water despite life-threatening consequences, each of the following hypotheses will be tested: (1) acetaldehyde normally limits drinking; (2) an effect of 4MP, or its interaction with ethanol reduces the animals' ability to acquire a conditioned taste aversion; (3) experience with the ethanol and water choice before treatment teaches the mice that ethanol is safe; and (4) by an unexpected mechanism, 4MP produces a state in which mice seek intoxication.
