The long-term objectives of this research are to understand the molecular basis of the actions of benzodiazepines and related compounds which act at the GABA/benzodiazepine receptor complex. These drugs are among the most widely prescribed compounds for the treatment of anxiety and sleep disturbances. They are also used as antiepileptic agents. The approach used in this proposal has been to isolate the proteins which are part of the GABA- benzodiazepine receptor complex, prepare antibodies to these proteins and identify the proteins biochemically and immunocytochemically. In addition, molecular probes to the and delta beta subunits of GABA/benzodiazepine receptor and other receptor molecules are being prepared to identify mRNA in cultured cells and from tissue for these receptors. The match between synthesis of mRNA and receptor number under conditions where receptor synthesis is induced and during development is to be studied. The effect of chronic administration of anxiolytics and antidepressants on receptor dynamics will be studied by comparing mRNA and receptor synthesis. The techniques to be used for mRNA determination are northern blotting and the levels of mRNA are quantitated with radiolabeled probes. ln this way, a clear relationship between receptor turnover and drug action will be established. The correlation of these changes with the therapeutic action of these drugs and their use in anxiety disorders and depression will be examined.
