The nervous system is capable of large, rapid alterations during repeated benzodiazepine dosing that can be measured as tolerance and dependence. Recent publications and preliminary data suggest that not all benzodiazepines produce the same patterns of tolerance or dependence. It is postulated that benzodiazepines of different structures can trigger various patterns of adaptive processes that could be detected as differing patterns of tolerance, dependence, and cross-tolerance. This will be studied by treating rats with a standard flurazepam treatment known to produce tolerance to benzodiazepine-induced motor impairment and anticonvulsant actions. These rats will be used to test for cross-tolerance using 8 benzodiazepines selected for their structural characteristics, or because of other data suggesting unusual patterns of tolerance or dependence. Based on previous work, tolerance will be sought for the anticonvulsant activity against the chemical convulsant pentylenetetrazol, and for locomotor impairment. These drugs, as well as flurazepam, will be compared in direct tolerance testing. Each will be given to rats for 4 weeks, then tolerance will be measured to the different drug actions. Physical dependence will also be examined, using the precipitated abstinence syndrome produced by a benzodiazepine antagonist, flumazepil (Ro15-1788). As patterns of tolerance, cross-tolerance and dependence emerge, various benzodiazepines will be chosen for further studies of cross- tolerance. The mechanisms that are the basis of tolerance and dependence remain unknown. Down-regulation of brain benzodiazepine receptors will be examined in rats treated with the various benzodiazepine, and data compared to previous results in flurazepam-treated tolerant rats. Receptors will be studied in brain homogenates, and also by quantitative receptor autoradiography, which was used to localize areas of downregulation in flurazepam-treated rats. To further examine possible mechanisms, an in vitro assay for receptor-coupled chloride ion flux was developed. This will be used to examine changes in the benzodiazepine receptor/GABA receptor/C1- channel complex, which is the machinery of GABA receptor- coupled inhibitory function, the site of acute benzodiazepine actions, and likely to be involved in chronic benzodiazepine actions. Using these various approaches, it should be possible to increase understanding of patterns of chronic benzodiazepine actions, and the mechanisms that are the basis of tolerance and dependence.
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