The benzodiazepines (BZs) are widely used drugs that are subject to abuse, and which can elicit tolerance and dependence. BZs act on neurons at specific BZ receptors which are actually modulatory sites on the receptors for GABA, the major inhibitory neurotransmitter. BZs increase GABA-mediated Cl conductance. However, all BZ/GABA receptors are not identical, and all BZs do not interact with their receptors uniformly. This variability is reflected in the tolerance that occurs during chronic treatment. For example, tolerance develops more rapidly for some measures of drug action than others, and there are differences among the BZs in degree and/or rate of tolerance development. Current work on this project has uncovered another aspect of non-uniformity of BZ tolerance. Rats that had all received the same one week flurazepam treatment were tolerant to some, but not other BZs. Thus, there may be differences among these drugs in their ability to cause tolerance, and in their ability to circumvent tolerance at the time of testing. The proposed research will seek to understand BZ tolerance at the time of testing. The proposed research will seek to understand BZ tolerance by comparing results of behavioral testing and three types of biochemical analyses. Several selected BZs will be tested after flurazepam treatments of varying lengths (to produce varying degrees of tolerance), and after treatment with certain other BZs. The patterns of tolerance and cross-tolerance may help define the requirements for a drug to allow tolerance to be displayed. Tolerance will be evaluated using several measure of anticonvulsant effects, and measures of drug-induced motor impairment. This will show if the expression of tolerance to all, or only some BZ actions is dependent on the drug used for testing. The role of the BZ/GABA receptor will be explored using two methods already shown to be useful in studies of BZ tolerance; specific binding of radio labelled BZ to receptors on neuronal membranes and a 36Cl flux assay to measure responsiveness to GABA and BZs. In addition, the expression of mRNA for the many isoforms of the GABA receptor subunits will be examined. Data from the behavioral and the three biochemical experiments will be examined, and the patterns of changes over time and among brain regions will be compared. These data should help define the role of the GABA receptor in chronic BZ actions, and may show where the changes that accompany tolerance occur in the sequence between drug-receptor interaction and the immediate physiological response (increase of GABA-stimulated Cl flux).
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