14 - Pharmacogenetics of anxiolytic drugs and the GABA–benzodiazepine receptor complex

Summary

OVERVIEW

The benzodiazepines (BDZ) have proven to be both effective and controversial in the treatment of anxiety. Whilst giving rapid relief of anxiety, they have undesirable characteristics, such as the development of tolerance, dependence, withdrawal symptoms, and alcohol potentiation. New insights into the genetics of the BD2 receptor system may lead to the development of new drugs that act on the γ-aminobutyric acid (GABA) receptor complex and are devoid of the problems associated with the classical BDZs. This pharmacotherapeutic approach has gathered impetus following the discovery of the various subunits of the GABA receptor, which are thought to play an important role in the regulation of anxiety and the actions of anxiolytics, and which demonstrate differential brain expression. There are a number of genetic variations in the GABA-A receptor and its subunits that can have an effect on the pharmacology of anxiolytic drugs. The various permutations of the subunits in the composition of these receptors impact on the activity and efficacy of these drugs. A second level of complexity is introduced with the genetic variations in each of these subunits. Such variations can result in amino acid replacements, deletions or imperfect subunit construction at a protein level, thereby resulting in different receptor combinations. This chapter discusses the above with reference to recent evidence from animal and human studies, as well as the implications for future anxiolytic treatment strategies.

Introduction

Clinical anxiety is a common cause of morbidity in the general population (Weiller et al., 1998).