The GABA system in anxiety and depression and its therapeutic potential

doi:10.1016/j.neuropharm.2011.08.040

Neuropharmacology

Volume 62, Issue 1, January 2012, Pages 42-53

https://doi.org/10.1016/j.neuropharm.2011.08.040 Get rights and content

Abstract

In the regulation of behavior, the role of GABA neurons has been extensively studied in the circuit of fear, where GABA interneurons play key parts in the acquisition, storage and extinction of fear. Therapeutically, modulators of α₂/α₃ GABA_A receptors, such as TPA023, have shown clinical proof of concept as novel anxiolytics, which are superior to classical benzodiazepines by their lack of sedation and much reduced or absent dependence liability. In view of the finding that anxiety disorders and major depression share a GABAergic deficit as a common pathophysiology, the GABA hypothesis of depression has found increasing support. It holds that α₂/α₃ GABA_A receptor modulators may serve as novel antidepressants. Initial clinical evidence for this view comes from the significantly enhanced antidepressant therapeutic response when eszopicole, an anxiolytic/hypnotic acting preferentially on α₂/α₃ and α₁ GABA_A receptors, was coadministered with an antidepressant. This effect persisted even when sleep items were not considered. These initial results warrant efforts to profile selective α₂/α₃ GABA_A receptor modulators, such as TPA023, as novel antidepressants. In addition, GABA_B receptor antagonists may serve as potential antidepressants.

This article is part of a Special Issue entitled ‘Anxiety and Depression’.

Highlights

► A GABA deficit is a hallmark of anxiety disorders and major depression. ► Modulators of α₂, α₃ GABA_A receptors are effective, non-sedative anxiolytics. ► Modulators of α₂, α₃ GABA_A receptors are proposed as novel antidepressants. ► Eszopiclone co-therapy supports the novel concept of GABAergic antidepressants.

Section snippets

Introduction: inhibitory networks

Following Sherrington’s recognition of neural inhibition as an active process (Sherington, 1908) and Eccle’s analysis of the physiology of inhibitory synapses (Eccles, 1964), the interest in inhibitory neurons has shifted to their role in neural circuits and the regulation of behavior. Complex brains have developed special mechanisms for the grouping of principal cells into temporal coalitions of local and distant networks, the inhibitory interneuron network (Buzsaki and Draguhn, 2004). By

Anxiety, fear and depression

Anxiety and depression are considered to be the most common outcomes of repetitive stress in humans and animals. Models of anxiety delineate two components: Fear mechanisms are thought to have evolved to enable us to shift our focus at the first suggestion of a danger and alter behavior to avoid or remove ourself from an immediate or anticipated explicit threat. Anxiety relates to risk assessment of a potential threat and crucially involves uncertainty as to the expectancy of the threat, is

Neuroimaging of anxiety and depression in humans

Studies in the field of affective cognitive neuroscience indicate that the amygdala–prefrontal circuitry is centrally involved in enabling both representations of emotional salience of stimuli and the top–down control mechanisms to influence associative, attentional and interpretative processes (Bishop, 2007). This circuitry is thought to be disrupted in anxiety. The functional connectivity between these two regions is inversely related to trait anxiety (Kienast et al., 2008), with the amygdala

Common treatment responses in anxiety disorders and depression

Symptoms of both anxiety and depression frequently respond to the same drug treatments which points to common neuronal dysfunctions in both disorders. A common response is evident for different classes of drugs including selective serotonin reuptake inhibitors (SSRIs), buspirone and also glutamatergic drugs such as ketamine and riluzole.

The fear circuit and the vocabulary of GABA neurons

The amygdala is the site for formation and storage of fear memories and extinction memories (LeDoux, 2000, LeDoux, 2007, Davis, 2000). It differs from many other brain areas by the low neuronal firing due to a strong inhibitory tone (Bordi et al., 1993, Pare and Collins, 2000). When a signal indicates threat, the “silence” is broken and excitatory neurons activate down stream defensive circuits (Quirk et al., 1995, Repa et al., 2001, Ehrlich et al., 2009) Conversely, signals which don’t predict

Dopamine gating of limbic processing: role of GABA

Under stress and in emotionally-charged conditions, DA, released from the ventral tegmental area (VTA)-pathway, potentiates amygdala function and enhances aversive conditioning. In the lateral amygdala, DA gates LTP induction by directly suppressing GABAergic feedforward inhibition (Bissière et al., 2003). The release of GABA is attenuated through presynaptic D2 receptors. A depolarizing action on inhibitory upstream interneurons through postsynaptic D2 receptors may also contribute (Bissière

GABA implicated in SSRI actions

Emotionality is strongly influenced by serotonin (Cools et al., 2007) in line with the treatment of anxiety disorders and depression with SSRIs. Although short-term SSRI treatment fails to be beneficial in animal models and in man (Burghardt et al., 2004, Shen et al., 2010, Anderson et al., 2008), the therapeutic effect of chronic SSRI in anxiety disorders and depression may, at least in part, entail a GABAergic component in view of both disorders displaying a GABAergic pathophysiology (see

Anxiety disorders and major depression: GABAergic deficits in patients

GABA is a crucial set point for anxiety states. Drug-induced enhancement of GABA transmission (benzodiazepines, tiagabine, neurosteroids) is anxiolytic (Argyropoulos et al., 2000, Pollack et al., 2005, Baldwin et al., 2005, Rupprecht et al., 2009, Durant et al., 2009), while a reduction of GABA transmission, as shown in man by the administration of a benzodiazepine site partial inverse agonist (FG7142), precipitates anxiety (Horowski and Dorow, 2002). In panic disorder, a pathophysiological GABA

GABAergic deficits are causal for anxiety- and depression-like behavior in animals

Pharmacological and genetic studies implicate GABA-receptor dysfunction as causal predisposition for both anxiety and depression. The benzodiazepine partial inverse agonist FG7142 induces anxiety in humans (Horowski and Dorow, 2002) and animals (Drugan et al., 1985), but also induced learned helplessness (Drugan et al., 1985). Learned helplessness was associated with a GABAergic deficit based on reduced release of GABA and increased release of glutamate in hippocampal slices (Petty and Sherman,

GABA and neurotrophic support

Driven by the evidence of depression- or stress-associated neural atrophy, depression research has focused on neurogenesis and neurotrophic support (Manji et al., 2000). Various antidepressant drugs (Santarelli et al., 2003, McEwen and Olie, 2005, Duman and Monteggia, 2006, Li et al., 2011) were found to enhance neurogenesis (Malberg and Duman, 2003) and up-regulate neurotrophins such as BDNF (Duman and Monteggia, 2006). Similarly, proliferation, maturation and synaptic integration of

Novel GABA anxiolytics, validated in humans

The search for novel anxiolytics, which are devoid of the deficits of classical benzodiazepines, have provided a fresh impetus on improving the therapy of anxiety disorders. However, only a few compounds have been validated in human proof of concept studies. They include TPA023, eszopiclone, ocinaplon and the indirectly acting XBD173, a TSPO ligand (Table 2).

GABA_A receptor modulators in depression

A beneficial effect of GABAergic drugs in depression would be expected based on the findings in patients of 1) a deficit in cortical GABA levels (Sanacora et al., 1999, Sanacora et al., 2000, Hasler et al., 2007) 2) a deficit in cortical GABA-A receptors (Klumpers et al., 2010) and 3) a deficit in the number of cortical GABA neurons (Rajkowska et al., 1999). In addition, in animals, a partial GABA-A receptor deficit (γ₂^+/− and α₂^+/− mice) triggers depression-like behavior (Shen et al., 2010,

GABA_B receptor modulators in anxiety and depression

With GABA being the primary inhibitory neurotransmitter, besides GABA_A receptors, metabotropic GABA_B receptors are implicated in diverse behavioral states (Ulrich and Bettler, 2007, Enna, 2007, Cryan and Slattery, 2010), as exemplified as by the GABA_B-dependent gating of LTP in the lateral amygdala, as described above. The interest in the role of GABA_B receptors in emotion regulation was strengthened by the recognition that GABA_B1 deficient mice show anxiety- and panic-like behavior.

Conclusion

In the control of emotionality, a GABAergic deficit appears to be a common denominator of anxiety disorders and major depression, which points to a potential GABAergic therapeutic approach in both disorders. In the therapy of anxiety disorders, modulators of α₂α₃ GABA_A receptor subtypes such as TPA023, have found initial clinical proof of concept as anxiolytics without sedation and with much reduced dependence liability as compared to classical benzodiazepines. Ligands of TPSO, which enhance

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ReviewThe GABA system in anxiety and depression and its therapeutic potential

Abstract

Highlights

Section snippets

Introduction: inhibitory networks

Anxiety, fear and depression

Neuroimaging of anxiety and depression in humans

Common treatment responses in anxiety disorders and depression

The fear circuit and the vocabulary of GABA neurons

Dopamine gating of limbic processing: role of GABA

GABA implicated in SSRI actions

Anxiety disorders and major depression: GABAergic deficits in patients

GABAergic deficits are causal for anxiety- and depression-like behavior in animals

GABA and neurotrophic support

Novel GABA anxiolytics, validated in humans

GABAA receptor modulators in depression

GABAB receptor modulators in anxiety and depression

Conclusion

Pharmacol. Therap.

Adv. Pharmacol.

Europ. Neuropsychopharm.

Biol. Psychiatry

Trends Cogn. Sci.

Biol. Psychiatry

Trends Pharmacol. Sci.

Adv. Pharmacol.

Drug Discov. Today

Eur. J. Pharmacol.

Biol. Psychiatry

Neuron

Biol. Psychiatry

Biol. Psychiatry

Europ. Neuropsychopharm.

Trends Neurosci.

Biol. Psychiatry

Neuron

Trends Neurosci.

Prog. Brain Res.

Neuron

Curr. Biol.

Biol. Psychiatry

Pharmacol. Biochem. Behav.

Neuron

DSMIV Diagnostic and Statistical Manual

Different lateral amygdala outputs mediate reactions and actions elicited by a fear-arousing stimulus

Nat. Neurosci.

Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines

J. Psychopharmacol.

Anxiogenic properties of an inverse agonist selective for α3 subunit-containing GABAA receptors

Br. J. Pharmacol.

TPA023, an agonist selective for α2- and α3-containing GABAA receptors, is a non-sedating anxiolytic in rodents and primates

J. Pharm. Exp. Ther.

In vitro and in vivo properties of MRK-016, a GABAA receptor alpha5 subtype-selective inverse agonist

J. Pharm. Exp. Ther.

Contributions of GABAA receptor subtype selectivity to abuse liability and dependence potential of pharmacological treatments for anxiety and sleep disorders

CNS Spectr.

Reducing abuse liability of GABAA/benzodiazepine ligands via selective partial agonist efficacy at alpha1 and alpha2/3 subtypes

J. Pharm. Exp. Ther.

Neural systems underlying approach and avoidance in anxiety disorders

Dialogues Clin. Neurosci.

NMDA receptor blockade at rest triggers rapid behavioral antidepressant responses

Nature

Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology

J. Psychopharmacol.

Evidenced-based pharmacological treatment of generalized anxiety disorder

Int. J. Neuropsychopharmacol.

RO4938581, a novel cognitive enhancer acting at GABAA alpha5 subunit-containing receptors

Psychopharmacology (Berl.)

Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion

Eur. J. Pharmacol.

Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior

Proc. Natl. Acad. Sci. USA

Trait anxiety and impoverished prefrontal control of attention

Nat. Neurosci.

Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition

Nat. Neurosci.

Single-unit activity in the lateral nucleus of the amygdala and overlying areas of the stiatum in freely behaving rats: rates, discharge patterns and response to acoustic stimuli

Behav. Neurosci.

Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder

Am. J. Psychiatry

Review
The GABA system in anxiety and depression and its therapeutic potential

GABA_A receptor modulators in depression

GABA_B receptor modulators in anxiety and depression

Anxiogenic properties of an inverse agonist selective for α₃ subunit-containing GABA_A receptors

TPA023, an agonist selective for α₂- and α₃-containing GABA_A receptors, is a non-sedating anxiolytic in rodents and primates

Contributions of GABA_A receptor subtype selectivity to abuse liability and dependence potential of pharmacological treatments for anxiety and sleep disorders

An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABA_A alpha5 receptors with cognition enhancing properties

Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the α₅ subunit of the GABA_A receptor