Ethanol withdrawal is characterized by subjective symptoms such as anxiety. Typically these symptoms occur earlier and last longer than overt physical signs of withdrawal. Because they are subjective, their relevance to drug dependence has been difficult to study in animal models. These experiments will use a pentylenetetrazol (PTZ) discrimination paradigm to quantify and detect symptoms of withdrawal from ethanol in animals. Rats can be trained to discriminate the stimulus properties of PTZ. Drugs that minimize or block the PTZ stimulus correspondingly provoke or diminish anxiety in humans. Furthermore, spontaneous or precipitated withdrawal from benzodiazepines produces a PTZ-like stimulus. These observations suggest that the discrimination of PTZ may be a suitable model for investigating subjective events related to dependence/withdrawal phenomena for ethanol. The primary objective of this research is to establish the degree to which withdrawal from ethanol produces internal stimuli that mimic those of PTZ in rats previously trained to discriminate PTZ. Further objectives include establishing that withdrawal can be detected more readily by the PTZ discrimination than by measuring overt signs; that the intensity of withdrawal signs and symptoms can be related to dose and duration of ethanol administration; and that anxiolytic and sedative-hypnotic drugs share features of cross-dependence with ethanol as measured by the PTZ discrimination method. Rats will be trained to select one lever after PTZ injections and a second lever after saline injections. After training, they will receive chronic ethanol administrations by gavage. Subsequently, ethanol administrations will be halted, and subjects will be tested for detection of the PTZ-like stimulus and observed for overt signs of withdrawal. Additional experiments will determine the degree to which ethanol, pentobarbital, diazepam, clinidine, morphine and narcotic antagonists modify detection of the PTZ-like stimulus during ethanol withdrawal. These experiments are significant because they will provide a model for objectively quantifying a subjective symptom of drug withdrawal in animals, and they will provide a novel tool to investigate behavioral and biological factors in ethanol dependence.
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