Role of the GABA—Benzodiazepine Receptor Complex in Stress

Abstract

An appreciation of the structure and function of the GABAA-benzodiazepine receptor-chloride ionophore complex is necessary in order to understand the therapeutic mechanism of action of several major classes of anxiolytic and sedative-hypnotic drugs. The chapter provides the background necessary to appreciate these structural and functional considerations. Studies reporting that genetic differences in the density of central benzodiazepine receptors exist between strains of animals differing in the traits of emotionality and fearfulness are presented. The demonstration, isolation, and synthesis of several inverse agonists have spurred theoretical speculation about the existence of endogenous ligands for the benzodiazepine receptor, as well as a role for this receptor in normal and pathological responses to stress. This chapter selectively reviews studies describing the plasticity of the benzodiazepine-GABA receptor complex in response to environmental stress. Several of these stress paradigms were naturalistic ones showing that the application of specific stressors during the early stages of an animal’s development results in enduring changes in benzodiazepine receptor sensitivity and behavior in the adult animal. There are also data showing that the benzodiazepine receptor is involved in the mediation and modulation of aggressive behavior. The potential relevance of these observations to child psychiatry is obvious. Evidence implicating peripheral hormones in the regulation of central benzodiazepine receptor sensitivity in response to stress is presented. A stressinduced modification of the complex would suggest that adaptive responses may be accompanied by changes in γ-aminobutyric acid (GABA)ergic transmission that are mediated postsynaptically; some of these changes appear to occur rapidly (i.e., within 1 min of exposure to the stress) and may reflect post-translational modification of the complex. Most of the data on the benzodiazepine receptor and its modification by environmental stress were obtained with classical in vitro techniques, especially filtration-binding assays. These techniques are performed under conditions that are not physiological with respect to temperature and salt concentrations; they disrupt the local neuronal circuitry involved in the regulation of benzodiazepine receptor sensitivity in the intact animal. Therefore, an in vivo approach to the measurement of benzodiazepine receptors in intact animals that avoids the artifacts associated with in vitro and ex vivo techniques has been developed. The method involves the intravenous injection of a tracer quantity of the radiolabeled antagonist Ro 15-1788. Using this in vivo approach, a relationship was shown between benzodiazepine receptor occupancy and the pharmacological potencies of several benzodiazepines. The application of this method to studying the effects of environmental stress and the mechanism of stress-induced modifications of binding are also reviewed.