This research will explore the pharmacology of flurazepan and other benzodiazepines as it relates to tolerance and dependence. We have shown that the central nervous system (CNS) is capable of a large, rapid adaptation to benzodiazepine exposure, even with rather low doses. Studies of receptor down-regulation have allowed some understanding of molecular mechanisms involved. Down-regulation of benzodiazepine receptors will be studied further using light microscopic autoradiography to localize sites of changes in receptor density. Previously, a correlation between receptor down-regulation and tolerance was found. Now, receptor regulation will be studied in animals treated with a method known to cause physical dependence to determine whether receptor regulation might contribute to dependence. Abstinence will be studied in withdrawing animals and in those given R015-1788, a benzodiazepine antagonist, to precipitate abstinence. Recent reports have shown that benzodiazepine receptors are present on pre- and postsynaptic neuronal membranes. Pre- and postsynaptic membrane enriched preparations will be used to determine if there is a selective pre- or postsynaptic localization of down-regulation. Possible involvement of receptors on adrenergic nerve terminals will be evaluated by studying the effects of intracerebroventricular 6-hydroxydopamine on subsequent receptor down-regulation, and on tolerance development. Drug effects on GABA-mediated C1- flux will also be studied in hippocampal slices that have been preloaded with radioactive chloride. Effects of benzodiazepines, Ro15-1788, and of pentobarbital will be studied to evaluate tolerance and dependence in this system. In behavioral studies, we will continue to study the dose and time requirements for producing physical dependence. Dependence due to flurazepam, diazepam and clonazepam will be compared. Because of the large autonomic component of precipitated abstinence, the effects of pretreatment with adrenergic blocking drugs, and changes in blood pressure and heart rate during abstinence will be studied. By using these various approaches, and comparing the results, we hope to continue to learn what mechanisms of adaptation are used by the CNS during chronic benzodiazepine exposure, and how these are manifest as tolerance and dependence.
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