Targeting the GABAB receptor for the treatment of depression and anxiety disorders

Abstract

The GABAB receptor is a functional heterodimer comprising the GABAB1 and GABAB2 subunits, with the GABAB1 subunit displaying two major isoforms, GABAB(1a) and GABAB(1b). Since the discovery of the GABAB receptor by Bowery in 1980, preclinical and clinical findings have strongly implicated the GABAB receptor in depression and anxiety disorders. Indeed, postmortem and clinical studies have highlighted a key role for the GABAB receptor in mood disorders. In parallel, pharmacological and genetic preclinical studies have confirmed that the GABAB receptor can modulate anxiety and depression-related behaviours. Despite the literature clearly linking GABAB receptor dysfunction with depression and anxiety disorders, GABAB receptor-based drugs have not yet been approved for their treatment. One of the main reasons for this is that drugs targeting the whole GABAB receptor may induce several major side effects. However, positive allosteric modulators and more recently, negative allosteric modulators of the GABAB receptor have been developed, and these could represent future therapeutic approaches for depression and anxiety disorders. Moreover, recent studies suggest that proteins interacting with the GABAB receptor could also be valid targets for the development of GABAB receptor-based drugs. This chapter will review the preclinical and clinical evidence for the GABAB receptor as a therapeutic target in the treatment of depression and anxiety disorders, and will outline some of the challenges that need to be overcome before GABAB receptor-based drugs can be used for this purpose in the clinic.