ENVIRONMENTAL STRESS-INDUCED FUNCTIONAL MODIFICATION OF THE CENTRAL BENZODIAZEPINE BINDING-SITE

The central benzodiazepine binding site mediates the therapeutically r elevant pharmacologic actions of benzodiazepine agonists, including re ducing anxiety, sedation, muscle relaxation, and antagonism of seizure production. Benzodiazepines potentiate the ability of gamma-aminobuty ric acid (GABA) to promote membrane chloride ion conductance by bindin g reversibly to a distinct site on the GABA(A) receptor complex. Altho ugh the role of this central benzodiazepine binding site in mediating the pharmacologic actions of benzodiazepine agonists has been shown co nclusively, its participation in an animal's response to stress is les s certain. Data are reviewed consistent with an environmental stress-i nduced modification of the structure and function of the central benzo diazepine binding site. Modifications show brain anatomic regional sel ectivity. The mechanisms of these modifications include rapid enzyme-m ediated phosphorylations of the GABA(A) receptor complex and the selec tive transcription of individual polypeptide subunits. The potential r elevance of the data on environmental stress-induced functional modifi cations of the central benzodiazepine binding site to the development of newer medications and improved understanding of the pathophysiology of stress-related neuropsychiatric disorders is discussed.