GABAB Receptors: Anxiety and Mood Disorders
Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, acts at the ionotropic GABAA and GABAC receptors, and the metabotropic GABAB receptor. This chapter summarizes the studies that have investigated the role of the GABAB rece
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Contents 1 Introduction 2 Role of the GABAB Receptor in the Modulation of Anxiety 2.1 Effects of GABAB Receptor Agonists and Positive Allosteric Modulators on Anxiety-Like Behaviour 2.2 Effects of GABAB Receptor Loss of Function and GABAB Receptor Antagonists on Anxiety-Like Behaviour 3 Role of the GABAB Receptor in Depression and Antidepressant Action 3.1 Effects of GABAB Receptor Agonists on Depression-Like Behaviour 3.2 Effects of GABAB Receptor Blockade or Loss of Function on Depression-Like Behaviour 4 Clinical Evidence of the Role of GABAB Receptor in Mood Disorders 5 Conclusions and Perspectives References
Abstract Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, acts at the ionotropic GABAA and GABAC receptors, and the metabotropic GABAB receptor. This chapter summarizes the studies that have investigated the role of the GABAB receptor in stress-related psychiatric disorders including anxiety and mood disorders. Overall, clinical and preclinical evidences strongly suggest that the GABAB receptor is a therapeutic candidate for depression and anxiety disorders. However, the clinical development of GABAB receptor-based drugs to treat these disorders has been hampered by their potential side-effects, particularly those of agonists. Nevertheless, the discovery of novel GABAB receptor allosteric modulators, and increasing understanding of the influence of specific intracellular GABAB receptor-associated proteins on GABAB receptor activity, may now pave the way towards GABAB receptor therapeutics in the treatment of mood and anxiety disorders. D. Felice, J. F. Cryan (*), and O. F. O’Leary (*) Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland APC Microbiome Ireland, University College Cork, Cork, Ireland e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 Curr Topics Behav Neurosci https://doi.org/10.1007/7854_2020_171
D. Felice et al.
Keywords Anxiety · Depression · GABAB receptor · Hippocampal neurogenesis · Mood · Stress · Stress resilience
1 Introduction The inhibitory action of GABA is mediated by the ionotropic GABAA and GABAC receptors, and the metabotropic GABAB receptor. The GABAA receptor is bicuculline-sensitive and the subsequent opening of its transmembrane channel which is permeable to chloride mediates rapid neuronal inhibition in the adult brain. In 1979, Norman Bowery and colleagues published the discovery of a novel type of GABA receptor that was described as being “atypical” and insensitive to the GABAA receptor antagonist bicuculline (Bowery et al. 1979). Baclofen was identified to be a potent and selective agonist of this novel receptor, and in 1980 it was demonstrated that baclofen acting on this novel receptor decreased neurotransmitter release in the central nervous system (Bowery et al. 1980). This atypical receptor described by Bowery and colleagues would later be referred to as the GABAB receptor (Hill and Bowery 1981). The GABAB receptor is a G-protein-coupled receptor that inhibits adenylate cyclase
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