The research in this proposal aims to validate a new hypothesis on tolerance and dependence to ethanol using a new animal model. This hypothesis states that acute and chronic tolerance are distinct phenomena with different neurochemical mechanisms and time courses of development and decay. Chronic tolerance and dependence are stated to have the same underlying mechanism and a similar time course of development and decay. Our animal model consists of automated intragastric infusions of ethanol delivered 3-4 times daily. Subjects for the study will be male rats with indwelling gastric catheters. Experiment I will evaluate and compare several measures for quantitating tolerance and withdrawal: heart rate, neuromuscular transmission in the tail, tremor, swim performance, startle response and body temperature. Necessity of using both a lab chow and an equicaloric carbohydrate control (dextrin-maltose) will be evaluated. Using heart rate as the dependent measure, Experiment II will examine the rate of development of acute and chronic tolerance with respect to dose and duration of treatment. Threshold dose and maximal level for both types of tolerance will be determined. Experiment III will examine the relationship between tolerance and dependence. Rats will be infused with 6, 8, 10 or 12 g/kg/day and sensitivity to ethanol (0.3-2.6 g/kg) will be assessed every 3-4 days. Contribution of metabolic tolerance and breath and brain ethanol levels will also be determined in this study. During withdrawal animals will be tested every 4-10 hours for 2 days; decay of tolerance will be evaluated over the course of 9 days. Experiment IV will examine the effect of duration and schedule of treatment. The effect of 11 g/kg ethanol for 8-24 days on levels of tolerance and dependence will be evaluated. We will also examine the development of these phenomena in animals given ethanol treatment on a repeating cycle of 2 days of treatment followed by 2 non-treatment days. Lastly, we will examine the development of acute and chronic tolerance, and dependence when daily ethanol treatment is in divided fractions compared to a continuous infusion. In conclusion, the proposed studies will characterize and determine the relationship between tolerance and dependence. These data will also provide us with information to determine whether similar mechanisms are involved in these phenomena and will provide a basis for studies aimed at elucidating the underlying mechanisms of them. Furthermore, this work may significantly alter our outlook and approach for the treatment and prevention of alcohol abuse and alcoholism in man.
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