Benzodiazepines (BZs), which are among the most widely prescribed psychoactive drugs, are subject to abuse, and can cause tolerance and dependence. Though BZs act by binding to specific neuronal receptors, the binding site is not that of a neurotransmitter. Rather, it is a modulatory site on the receptor for GABA, the major inhibitory neurotransmitter. BZs increase the ability of GABA to open Cl channels, increasing inhibitory neurotransmission. BZ/GABA receptors show remarkable molecular heterogeneity. BZs do not all interact with the receptors uniformly, and this is reflected in tolerance and dependence. Tolerance develops more rapidly for some drug actions than others, and there are differences among BZs in degree and rate of tolerance or dependence development. Even after a given BZ treatment, the degree of tolerance shown depends on the particular BZ chosen for testing. Differences among BZs are probably due to differing interactions of particular BZs with GABA receptors during and after chronic treatment. This project will study the role of changes in BZ/GABA receptors in tolerance and physical dependence. Several drugs that act at the BZ/GABA receptor will be examined in rats treated with either flurazepam or with diazepam. These treatments are known to cause differing patterns of tolerance and dependence, as well as differing neurochemical changes. The BZ/GABA receptor will be studied by specific binding of BZs to tissue obtained from particular brain regions of tolerant rats. Changes in BZ/GABA receptor numbers and characteristics may result from modifications in the combinations of subunits that neurons assemble to form these receptors. Regional brain mRNA expression for the many GABA receptor subunits will be examined and compared to the dose and time requirements for producing tolerance and dependence. The protein product will also be examined using an antibody specific for one of the major subunits of the GABA receptor. Results from the behavioral and biochemical experiments will be examined, and the patterns of changes over time and among brain regions will be compared to help define the role of the GABA receptor in chronic BZ actions.
Showing the most recent 10 out of 43 publications
