Work will continue on the use of the gastric fistula rats for the study of sedative, hypnotics and antianxiety drugs with the particular end of identifying partial agonists and agents with unique pharmacologic and toxicologic profiles. Dose response relationships of the ability of several prototypic sedative, hypnotic and antianxiety drugs will be obtained. The configuration of dose response lines and the relative potencies of prototypic sedative, hypnotic, and antianxiety drugs will be investigated in non-tolerant, non-dependent as well as in tolerant dependent rats and in abstinent dependent rats. Further comparative studies of how alcohol interacts with sedative, hypnotic and antianxiety drugs will be extended to several benzodiazepines (Oxazepam, Lorazepam, Clorazepate and Flurazepam). In this regard a superior and safer sedative, hypnotic drug will be one that has a ceiling effect, a limited ability to produce tolerance and dependence and one that would have a minimal interaction with alcohol. The fistula rat may be especially useful for chronic toxicity studies. The observation that diazepam may induce fibroadenomas in fistula rats will be pursued with endocrine studies measuring its effect in plasma estrogen and LH levels. Urine of the rats who have been chronically treated with diazepam will be examined for metabolites which have the potential for being pro-carcinogens or carcinogens.
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