Anxiety disorders and GABA neurotransmission: a disturbance of modulation

Summary & key facts

This review says anxiety disorders are linked to problems in how brain circuits control emotional responses to threats. It describes a balance between bottom-up signals from the amygdala (showing possible threats) and top-down control from the prefrontal cortex. The inhibitory neurotransmitter GABA and its GABAA receptor subtypes and modulators — including brain-made neurosteroids whose production is influenced by stress — play key roles in this modulation. The paper highlights these mechanisms as possible targets for new psychological and drug treatments, while noting the idea is based on multiple lines of neuroscience evidence rather than a single proof.

Key facts:

• Anxiety disorders are described as a disturbance in the modulation of brain circuits that regulate emotional responses to potentially threatening stimuli.
• Amygdala circuits include inhibitory networks of GABAergic interneurons, and GABA is important for controlling anxiety-related brain activity in both normal and pathological states.
• The GABAA receptor has allosteric sites that let other molecules change how much it inhibits neurons; those sites are the molecular targets of main classes of anxiety drugs.
• Changes in endogenous modulators of GABAA receptors or changes in GABAA subunit composition are proposed mechanisms that could lower neuronal inhibition in pathological anxiety.
• Neurosteroids are made in the brain, act as allosteric modulators of GABAA receptors, and their synthesis is regulated by stress and anxiogenic (anxiety-producing) stimuli, making the neurosteroid–GABAA axis a potential target for modulatin
• The review frames anxiety as a problem of emotional response regulation and suggests this view could guide development of psychological, behavioral, and pharmacological treatment strategies, but it synthesizes evidence from many studies rat

Abstract

Lines of evidence coming from many branches of neuroscience indicate that anxiety disorders arise from a dysfunction in the modulation of brain circuits which regulate emotional responses to potentially threatening stimuli. The concept of anxiety disorders as a disturbance of emotional response regulation is a useful one as it allows anxiety to be explained in terms of a more general model of aberrant salience and also because it identifies avenues for developing psychological, behavioral, and pharmacological strategies for the treatment of anxiety disorder. These circuits involve bottom-up activity from the amygdala, indicating the presence of potentially threatening stimuli, and top-down control mechanisms originating in the prefrontal cortex, signaling the emotional salience of stimuli. Understanding the factors that control cortical mechanisms may open the way to identification of more effective cognitive behavioral strategies for managing anxiety disorders. The brain circuits in the amygdala are thought to comprise inhibitory networks of γ-aminobutyric acid-ergic (GABAergic) interneurons and this neurotransmitter thus plays a key role in the modulation of anxiety responses both in the normal and pathological state. The presence of allosteric sites on the GABAA receptor allows the level of inhibition of neurons in the amygdala to be regulated with exquisite precision, and these sites are the molecular targets of the principal classes of anxiolytic drugs. Changes in the levels of endogenous modulators of these allosteric sites as well as changes in the subunit composition of the GABAA receptor may represent mechanisms whereby the level of neuronal inhibition is downregulated in pathological anxiety states. Neurosteroids are synthesized in the brain and act as allosteric modulators of the GABAA receptor. Since their synthesis is itself regulated by stress and by anxiogenic stimuli, targeting the neurosteroid-GABAA receptor axis represents an attractive target for the modulation of anxiety.

Topics

Neuroendocrine regulation and behavior Neuroscience and Neuropharmacology Research Stress Responses and Cortisol

Categories

Psychology Social Psychology Social Sciences

Tags

Amygdala Anxiety Anxiolytic Cognition Elevated plus maze GABAA receptor GABAergic Inhibitory postsynaptic potential Internal medicine Medicine Neuroscience Neurotransmission Prefrontal cortex Psychiatry Psychology Receptor

Conditions & symptoms

Anxiety Anxiety or worry