The proposed research has two broad aims: first, in an animal model of subjective drug effects, t will document parameters of tolerance to ethanol; second, it will explore the neurochemical basis for this tolerance. The proposed experiments use rats as subjects. They are taught to """"""""perceive"""""""" the effects of ethanol by use of drug discrimination methodology. For this training, subjects are given food-reinforcement for responding on a correct lever (ethanol-lever following ethanol, 1.0 g/kg; vehicle-lever following vehicle). After training to a criterion of 1 0 sessions in a row of correct lever selection, they will be tested with various doses of ethanol and other sedative-hypnotic and non-sedative-hypnotic drugs to determine substitution and blockade data for these agents. Subsequently, tolerance to the discriminative stimulus effects of ethanol will be established by administering ethanol twice daily in a nutritionally complete liquid diet. In a first series of experiments, parameters of this tolerance will be established as a function of dose (2 to 16% ethanol) and duration (one to ten days) of dosing. In a second series of experiments, parameters of cross-tolerance to other sedative-hypnotics (including barbiturates, trichloroethanol, benzodiazepines) and non-sedative-hypnotic drugs (including cocaine and narcotics) will be established. In a final series of experiments, the neurochemical basis of tolerance will be explored by determining the effects of tolerance on substitution and blockade patterns of drugs with known mechanisms of action (benzodiazepine agonists and inverse agonists; NMDA-channel blockers; serotonin receptor agonists and antagonists). In all experiments, concentrations of ethanol are determined by a breathalyzer technique such that pharmacokinetic and pharmacodynamic elements of tolerance can be distinguished. For this portion of the work, immediately following testing in the drug discrimination chambers, subjects are placed in sealed desiccant chambers. After mixing of exhaled air with ambient air has stabilized, a 1 ml sample is drawn from the environment, and ethanol concentration is determined by gas-chromatography with flame ionization detection. The proposed experiments are important because drug discrimination is widely regarded as an animal model of human subjective effects of drugs. Thus, tolerance in this model is likely to have impact on understanding changes in subjective phenomena that occur with high-dose ethanol intake. These results will also provide parameters for future studies that directly examine the role of tolerance in increased ethanol consumption.
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