Benzodiazepines are the most widely used and abused sedatives, hypnotics, anti-anxiety drugs and drugs used for muscular pain. These drugs are thought to act as agonists, partial agonists and as antagonists at several types of receptors. They produce an insidious form of physical dependence which is characterized by several types of precipitated and withdrawal abstinence syndromes which have the following signs and symptoms: seizure, rigidity and dyskinesias, affective disorders, tremors and autonomic disturbances. The general goal of this proposal is to identify pharmacologic principles which contribute to the dependence producing properties of the benzodiazepines and through these efforts help identify drugs which are safer and less dependence producing.
The specific aims are to identify those parts of the brain which are responsible for these signs of precipitated abstinence, discover which receptors are responsible for these signs, identify pharmacokinetic and dispositions properties of benzodiazepines which enhance their dependence producing properties through cummulation and define the role of gender in the production of physical dependence. Diazepam dependent rats will be used to identify the brain sites responsible for different abstinence signs by microinjecting the benzodiazepine antagonist, flumazenil, into various brain sites and observing the animals for both electrical and behavioral signs of abstinence. Dogs will be used to determine the effect of both duration and dose on the quality of the abstinence syndrome and its intensity. The impact of these two variables on the metabolism of certain benzodiazepines will be studied in the dog. Further studies will be conducted in both the dog and rat to determine how certain prototypic benzodiazepines are distributed on both a regional and subcellular basis in the brain.
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