The tolerance and dependence associated with chronic benzodiazepine administration are complicated phenomena, probably due to the complex interactions between specific benzodiazepines and the many different types of GABA/benzodiazepine receptors. The literature suggests at least three types of adaptive processes that may be related to tolerance: those involving regulation of GABA/benzodiazepine receptor number, turnover, and subunit composition of receptors; those involving post-translational modifications of the receptor; and those involving secondary changes in other transmitter systems. It has been found that benzodiazepine treatment can affect benzodiazepine binding site number and GABAA receptor subunit mRNA levels, though the relationship to tolerance is not clear. Experiments will examine the effects of chronic benzodiazepine treatments of the levels of GABAA receptor beta subunits. Time and region-dependent changes will be compared to previous results from behavioral, biochemical, receptor bind, and mRNA studies. Adaptive changes in specific sub-populations of brain benzodiazepine receptors will be studied using recently-reported selective ligands. This will examine the hypothesis, based on previous results, that there is a shift in benzodiazepine receptor subtype in tolerant brain tissue. Other experiments will examine one type of post-translational modification by evaluating a possible role for receptor glycosylation in regulating binding of selected drugs to the receptors, and the effects of chronic benzodiazepine treatment. The effect of deglycosylation on receptors is brain region specific, and differs for various benzodiazepines and other drugs that act at the GABA receptor. Thus, alterations in receptor glycosylation state could provide a basis for many of the changes found in GABA receptors during chronic benzodiazepine treatment. In each type of experiment, we will compare two chronic treatments (diazepam and flurozepam), as well as the time course of changes. This will provide the basis for evaluating the results in the context of previously- determined behavioral, biochemical and other measures of tolerance and dependence, and regulation of GABA/benzodiazepine receptors.
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