A COMPARISON OF TECHNIQUES TO INDUCE ALCOHOL DEPENDENCE AND TOLERANCE IN THE MOUSE

¹ National Institute of Alcohol Abuse and Alcoholism, National Institute of Mental Health, Chevy Chase, Maryland

Freund (Arch. Neurol. 21: 315-320,1969) first reported the induction of physical dependence upon alcohol in mice, reduced to 65% of their free feeding weight, after four days of restriction to a Metrecal or sucrose-alcohol diet in which 35% of the total calories were derived from alcohol. The present study attempted to compare the relative efficacy of the Freund Liquid Diet procedure with a behavioral technique, schedule-induced polydipsia for developing alcohol dependence in mice. Specifically, we were concerned with determining if equivalent alcohol consumption in the presence of an adequate diet would be effective in producing physical dependence, and if any differences between groups could be accounted for in terms of liver pathology. A replication of the Freund procedure yielded comparable data with respect to temporal distribution and volume of alcohol consumed. Mice in the Metrecal-alcohol and sucrose-alcohol groups showed tremor and convulsions upon removal of alcohol as was first described by Freund. The schedule-induced polydipsia procedure involved delivery of dry food pellets at 180-second intervals, in four daily sessions during which a 3, 6 or 10% alcohol solution was available as the only fluid. This procedure was effective in inducing the consumption of large quantities of fluid each day, approaching 40% of total body weight. Alcohol intake using this procedure (X = 0.58-0.71 ml of absolute alcohol; 14-24 mg/g) exceeded that observed with the Freund procedure (X = 0.45-0.46 ml of absolute alcohol; 15-18 mg/g). During the final replication of the polydipsia paradigm, high alcohol intake was sustained over periods of 7 to 14 days; however, no animal showed evidence of physical dependence during a 10-hour observation period after substitution of water for alcohol. Consequently, consumption of alcohol in amounts exceeding 15 mg/g or 0.50 ml of absolute alcohol per day for prolonged periods of time is not a necessary and sufficient condition to produce withdrawal signs and mice upon removal of alcohol. This observation was not easily interpreted in terms of the liver histopathology and cannot be attributed to differences in strain, age, amount and duration of alcohol intake or blood alcohol levels between the two groups. The severe nutritional deficiency in combination with profound weight loss found in the Freund replication mice given sucrose or Metrecal plus alcohol diets was the most obvious difference between the two groups. A second difference was the temporal pattern within which each group consumed alcohol. The unresolved questions raised by these data reemphasize that the critical determinants in the development of physical dependence upon alcohol are unknown and the nature of the addictive process remains a matter of conjecture.

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