Anxiety disorders and GABA neurotransmission: a disturbance of modulation

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.

Keywords: allosteric modulation; amygdala; neurosteroids; salience; γ-aminobutyric acid.

Figure 1

Neural circuits implicated in anxiety disorders. Notes: Green arrows: principal inputs to the BLA; orange arrows: principal outputs of the BLA; blue arrows: principal outputs of the CeA and BNST. Abbreviations: ACC, anterior cingulate cortex; BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; PFC, prefrontal cortex.

Figure 2

A GABAergic medial paracapsular intercalated cell in the mouse amygdala. Notes: Scale bar: 50 μm. Republished with permission of the Society for Neuroscience, from Different fear states engage distinct networks within the intercalated cell clusters of the amygdala, Busti D, Geracitano R, Whittle N, et al, J Neurosci, 31(13), 2011; permission conveyed through Copyright Clearance Center, Inc. Abbreviations: BLA, basolateral amygdala; CeA, central nucleus of the amygdala.

Figure 3

Electron micrograph of the GABA_A receptor isolated from a pig’s brain and stained with uranyl acetate. Note: In (A), the general field of the purified protein stained with uranyl acetate is shown. The receptors are circled in this image taken at an actual magnification of 33,000×; bar =20 nm. In (B), four receptor particles, typical of those exhibiting five-fold symmetry, are shown. (C) shows a rotationally averaged representation of the first particle in (B), in (C) the image is significantly enhanced. Reproduced from Quaternary structure of the native GABA_A receptor determined by electron microscopic image analysis, Nayeem N, Green TP, Martin IL, Barnard EA, Journal of Neurochemistry, 1994;62(2):815–818. Copyright © 2002, John Wiley and Sons. Available from: http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.1994.62020815.x/abstract.

Figure 4

Schematic representation of binding sites on the most common isoform of GABA_A receptor. Note: α1, β2, and γ2 represent the subunits of the most widespread isoform of the GABA_A receptor in the central nervous system. Abbreviations: BDZ, benzodiazepine; ETF, etifoxine; GABA, γ-aminobutyric acid; NS, neurosteroid.