Benzodiazepines are very useful and safe drugs when used alone in the treatment anxieties, sleep disorders, muscle pain, convulsions and alcohol withdrawal. They however can be very toxic when used with other central nervous system depressants and produce physical dependence when used chronically. Physical dependence on benzodiazepines is complex and involves many systems of the brain and results in many signs when they are withdrawn. Different benzodiazepines produce different therapeutic effects and different types of physical dependencies. It is also known that the recently found that diazepam and halazepam in large doses produce a dose related liver toxicity while other benzodiazepines (eg alprazolam) do not. The general aims of this proposal are to (1) find which parts of the brain and (2) which benzodiazepine receptors are responsible for the different signs of the abstinence syndrome. (3) Which administering benzodiazepines chronic increase the number of responsible receptors. (5) The benzodiazepine abstinence syndrome is thought to increase the need for benzodiazepines. The parts of the brain and the receptors responsible for this increased need will be identified. (6) Efforts will be made to find out if the hepatotoxicity seen in the dog is of importance in humans by studying liver function and free plasma levels of diazepam, alprazolam and their metabolites in patients being treated with these drugs chronically. To identify those parts of the brain and the receptor that are responsible for abstinence signs and symptoms, small amounts of specific agonist and antagonists will be injected into different brain sites of benzodiazepine abstinent and stabilized dependent rats and see if the different sign are decreased or increased. To help identify receptor characteristics responsible for dependencies, abstinence will be produced with graded doses of the antagonist, flumazenil, in dogs and rats dependent on graded doses of diazepam and its metabolites. Free brain levels of diazepam, its metabolites and flumazenil will be determined. These data and abstinence scores will be used to calculate the number and the affinity of the receptors. These studies may provide a rational basis for designing new and selective benzodiazepines which are safer and do not produce dependence.
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