Historical perspective and emergence of the GABAB receptor.

This chapter forms an introduction to the subsequent chapters in this volume which highlight the significance and potential therapeutic application of GABA(B) receptors. It is now 30 years since the GABA(B) site was first described in mammalian tissue. Since then much has emerged about its physiological role in the mammalian nervous system and its relationship to other neurotransmitter receptors. It appears to function at pre- and postsynaptic locations as both an auto- and a hetero-receptor where its activation modulates the membrane conductance of Ca(2+) and K(+). The receptor is G-protein coupled and was the first to be shown to exist, possibly in multiple forms, as a heterodimer. The primary agonist for the receptor is baclofen and this continues to be used therapeutically as a centrally active muscle relaxant. Other potential applications for agonists are suggested and positive allosteric modulators may provide an alternative and more effective approach. One application of an agonist, for which there are strong positive clinical data, is in gastroesophageal reflux disease where the receptor target is outside the brain. Antagonists of the GABA(B) receptor may also have therapeutic applications such as in cognitive deficits, affective disorders, and absence seizures but robust clinical evidence remains to be demonstrated. Each of these applications is also discussed in the chapters that follow.