There is growing evidence that a significant number of alcoholics are also abusers of benzodiazepines (BZD). One of the major clinical uses of BZD is the treatment of withdrawal from alcoholism. The use of BZD such as chlordiazepoxide (CDP) in treating alcoholism beyond detoxification may be inappropriate, especially for the combined alcohol/BZD addicts, because BZD are not only ineffective but are contraindicated due to their addiction potential and synergism with alcohol. Therefore, it is highly desirable and clinically relevant to learn about the long- term effects of the combined use of alcohol and BZD, as well as how these two drugs interact during chronic intake. Animal models are needed to circumvent ethical and humane considerations which dictate against intensive studies on combined drug dependence in man. Ethanol or CDP dependence will be induced in mice by chronic feeding of a liquid diet containing either drug. It is proposed to test the hypothesis that different durations of CDP intake and CDP doses can affect the following parameters differently: (a) development of CDP tolerance and ethanol cross-tolerance; (b) nature and severity (a scoring system will be used) of spontaneous or R015-1788-induced CDP withdrawal signs (R015-1788 is a BZD receptor antagonist); (c) increase in CDP metabolism after chronic diet treatment; (d) induction (if any) of ethanol metabolism; (e) long-term behavioral effects such as locomotor activities, runway and head-dipping activities. Since a better understanding of the phenomena of cross-tolerance and cross-dependence between ethanol and CDP, as well as the effects of combined ethanol/CDP intake is necessary for the better prevention and treatment of the combined drug abuse problems, the following investigations are also proposed: (1) determination of whether CDP-dependent mice are cross-dependent on ethanol; (2) investigation of the equivalence between ethanol tolerance and CDP cross-tolerance, and vice versa; (3) assessment of whether the development of cross-tolerance to CDP in ethanol-treated mice, and vice versa, is influenced by environmental factors; (4) development of a mouse model for combined alcohol/CDP dependence by chronic feeding of a liquid diet containing both drugs, and determination of the accompanying long-term effects such as tolerance, withdrawal reactions, and behavioral effects. The pharmacodynamic interactions resulting from chronic ethanol/CDP intake may produce these changes different from those elicited by either drug alone.

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National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Alcohol Biomedical Research Review Committee (ALCB)
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Research Institute on Alcoholism
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