DESENSITIZATION OF A GAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTOR IN RAT IS INCREASED BY CHRONIC TREATMENT WITH CHLORDIAZEPOXIDE - A MOLECULAR MECHANISM OF DEPENDENCE

When rats were made tolerant to the benzodiazepine tranquilizer chlord iazepoxide (CDPX) by its steady administration, a particular gamma-ami nobutyric acid type A (GABA(A)) receptor in cerebral cortex was modifi ed. Its rate of desensitization in the absence of CDPX was enhanced (3 -fold with 10 mu M GABA) below saturation with GABA, and the dependenc e of this rate on GABA concentration was changed from sigmoid to hyper bolic. This mimicked the effect of the presence of CDPX on desensitiza tion of the naive receptor. This receptor has been characterized by it s rapid desensitization (t(1/2) = 30 msec at saturation). in contrast, a different, slower desensitizing GABA(A) receptor, on the same membr ane, was unaffected, and the initial transmembrane halide exchange rat e of the faster desensitizing receptor was unaltered. In the presence of CDPX, the initial halide exchange rate of the modified receptor was enhanced, but the already enhanced desensitization rate was not alter ed. During chronic presence of CDPX and the development of tolerance, the total signal due to this receptor remained constant at the value b efore exposure. After discontinuation, the total signal decreased but could be restored to the original value by the presence of CDPX. It wa s postulated that dependence and withdrawal syndromes result from a de creased ratio of initial chloride flux rate to desensitization rate, c aused by an increase in desensitization. The contribution of this effe ct in vivo would depend on desensitization making a contribution to si gnal termination [or the fraction of receptors that are inactive (dese nsitized)]. in the quench flow experiments, the total signal due to th is receptor from naive rat did not depend much on GABA concentration o r the presence of CDPX because the result of increased channel opening was counterbalanced by increased desensitization. In contrast, the to tal signal of this receptor from tolerant rat was significantly increa sed by CDPX or increased GABA concentration. Differences between these experiments and measurements reported with other drugs could be expla ined if, in those experiments, the halide exchange rate, as well as it s desensitization rate, retained an enhanced value in the absence of t he drug.