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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatr. Mar 22, 2016; 6(1): 43-53
Published online Mar 22, 2016. doi: 10.5498/wjp.v6.i1.43
Cortical and subcortical gamma amino acid butyric acid deficits in anxiety and stress disorders: Clinical implications
Andrew W Goddard, Department of Psychiatry, UCSF Fresno Medical Education and Research Program, Fresno, CA 93701, United States
Author contributions: Dr. Goddard AW reviewed the literature and wrote the manuscript.
Conflict-of-interest statement: Royalties for manuscript production for UpToDate. No financial support for the current review paper.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Andrew W Goddard, MD, Professor of Psychiatry, Department of Psychiatry, UCSF Fresno Medical Education Program, 155 N. Fresno Street, Fresno, CA 93701, United States. agoddard@fresno.ucsf.edu
Telephone: +1-559-4996580 Fax: +1-559-4996581
Received: October 27, 2015
Peer-review started: November 3, 2015
First decision: December 4, 2015
Revised: December 18, 2015
Accepted: January 27, 2016
Article in press: January 29, 2016
Published online: March 22, 2016

Abstract

Anxiety and stress disorders are a major public health issue. However, their pathophysiology is still unclear. The gamma amino acid butyric acid (GABA) neurochemical system has been strongly implicated in their pathogenesis and treatment by numerous preclinical and clinical studies, the most recent of which have been highlighted and critical review in this paper. Changes in cortical GABA appear related to normal personality styles and responses to stress. While there is accumulating animal and human neuroimaging evidence of cortical and subcortical GABA deficits across a number of anxiety conditions, a clear pattern of findings in specific brain regions for a given disorder is yet to emerge. Neuropsychiatric conditions with anxiety as a clinical feature may have GABA deficits as an underlying feature. Different classes of anxiolytic therapies support GABA function, and this may be an area in which newer GABA neuroimaging techniques could soon offer more personalized therapy. Novel GABAergic pharmacotherapies in development offer potential improvements over current therapies in reducing sedative and physiologic dependency effects, while offering rapid anxiolysis.

Key Words: Brain imaging, Anxiogenesis, Gamma amino acid butyric acid, Anxiety disorders, Anxiolysis

Core tip: Preclinical and clinical studies strongly support the notion that impairments in gamma amino acid butyric acid (GABA) neurotransmission underpin human stress and anxiety disorders. Measurement of in-vivo brain GABA function with modern neuroimaging tools, such as proton magnetic resonance spectroscopy, in healthy and disease populations, has contributed greatly to this literature, and also offers the possibility of monitoring GABAergic anxiolytic therapy.



INTRODUCTION

Anxiety and stress disorders are a major public health problem. They are the most common mental health conditions in the United States with a 12-mo prevalence rate of 18%[1]. Moreover, in their lifetime, over 25% of the United States population is expected to suffer from at least one anxiety disorder[1]. Anxiety disorders are responsible for long-term morbidity, and are now thought to be even more chronic than either substance use or mood disorders[2]. Similar observations have been reported from surveys conducted around the globe[3-5]. Across these studies, another consistent finding was the disproportionate impact of clinical anxiety on women. Finally, the societal and economic impact of anxiety syndromes is remarkable. In 1990, for instance, the direct and indirect cost to the United States economy due to these disorders was $42.3 billion[6].

Over the last three decades, diagnostic assessment and treatment options for morbid anxiety have improved considerably. Despite many theories, however, the pathogenesis of these conditions remains unclear. With a deeper understanding of fear and stress neurocircuitry, and the availability of more sophisticated imaging and genetic analytic tools, progress is being made. Within the field, there has been an emerging emphasis on the role of amino-acid neurochemical systems, such as the amino-butyric acid [The gamma amino acid butyric gamma acid (GABA), the major inbibitory neurotransmitter in the central nervous system (CNS)] and its excitatory counterpart, glutamate, in anxiogenesis and anxiolysis. This review will examine the evidence implicating abnormalities in GABA neurotransmission in the genesis of stress and anxiety in health and disease. Key anxiety and stress disorders such as panic disorder (PD), generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD) will be reviewed through the lens of relevant animal models and human imaging studies implicating GABA deficits in anxiogenesis. The potential role of GABA in developmental anxiety will be mentioned, as will the evidence for GABA deficits in other neuropsychiatric syndromes in which anxiety is prominent. Finally, an overview will be provided of anxiolytic agents, which directly or indirectly support GABA neurotransmission, and which can address deficits in GABA functioning in the clinical disorders.

RESEARCH

A literature search was conducted using the PubMed and Thomson Web of Science v5.15 search engines. References were identified that directly related to the search terms, “GABA and clinical anxiety”, including several review papers. Preference for inclusion in the current paper was given to articles published after 2009. However, some key/landmark papers published prior to 2009 were also included.

GABA NEUROTRANSMISSION AND NORMAL ANXIETY

Several rodent models have highlighted the role of the GABA synthetic isoenzymes glutamic acid decarboxylase 65 (GAD65) and GAD67 in the expression of normal mammalian fear. For example, knockdown of GAD67 protein in the mouse amygdala impaired normal fear extinction and decreased sensitivity to the benzodiazepine anxiolytic, diazepam[7]. In another experiment, a genetic impairment in GAD65 expression was linked to decreased GABAergic transmission and plasticity in the lateral amygdala (LA), which, in turn, was associated with generalization of conditioned fear responses[8]. A study of male rats additionally demonstrated the importance of the sex hormone, 17-estradiol, as a promoter of GAD65 expression, with pharmacologic inhibition of 17-resulting in increasing expression of anxious behaviors (decreased open field exploration)[9].

Improvements in proton magnetic resonance spectroscopy (1H-MRS) technology and editing have led to the ability to quantify regional brain GABA concentrations, and other related amino acid metabolites, non-invasively. As a result, over the last 5 years, a number of studies applying these techniques in healthy humans have been published. These investigations have begun to define the relationships between normal human stress responses, personality type, and cortical GABA changes. For example, harm avoidance, as a normal human temperament trait, was observed to correlate positively with anterior cingulate cortex (ACC) GABA concentrations, and negatively with glutamate levels[10]. Evaluating extraversion/introversion and neuroticism in healthy subjects, another group reported a negative correlation between frontal GABA/creatine ratios (data acquired at 3 Tesla), and extraversion[11]. In another line of inquiry, acute psychological stress in healthy humans (threat of footshock) was associated with an acute decrease in prefrontal cortical GABA concentrations, similar to acute stress findings in the animal literature[12]. Investigating the impact of wellness interventions, such as yoga and walking, on cortical GABA, one group reported a relationship between improvements in stress level and mood, and increases in thalamic GABA levels, for yoga subjects only[13]. Other investigators using an fMRI/MRS assessment strategy, observed, in healthy humans, that lower insula cortex GABA levels and enhanced insula responses to interoceptive stimuli, together predicted higher levels of reported depressive affect[14]. However, studying female subjects, others did not observe a relationship between low insula GABA and inclination toward fearfulness[15].

Thus, cortical and subcortical GABA concentrations can be informative biological correlates of components of personality function and emotional processing, and appear to be change-sensitive markers of normal responses to acute stress and relaxation. It is foreseeable that routine assessment of inhibitory brain function in this manner is likely to enhance the effectiveness of early-intervention and prevention protocols designed to interrupt the genesis of chronic anxiety or depressive states.

GABA DEFICITS IN PD

Although the neurobiological mechanisms underlying this common and disabling psychiatric syndrome remain unclear, a range of preclinical and clinical findings have implicated disturbances in GABA function in its pathophysiology. Animal modeling work[16] has demonstrated that biochemically-induced GABA deficits in the dorsomedial hypothalamus (DMH) of rats predispose to sodium lactate-induced panic, also an important clinical feature of human PD[17]. Follow-up work with this particular model has observed that lactate sensitivity and other anxious rodent behaviors could be driven by loss of GABAergic inhibition to a local DMH and perifornical population of peptidergic orexin (ORX) neurons[18]. Thus, impaired GABA function may facilitate ORX neuronal hyperactivity, thereby leading to increased sympathetic activation, and panicogenesis.

Other animal models of chronic anxiety/panic have focused on deficits in functioning of synaptic GABAA receptors as a risk factor for anxiety-proneness. For example, genetically induced deficits (moderate reductions) in expression of GABAA receptor 2 subunits (by heterozygous knockdown or knockout), were associated with neophobic behaviors, behavioral inhibition, or exaggerated defensive responses to mild threat[19]. More recently, the same group demonstrated that 2-containing GABAA receptor subpopulations are also implicated in the defensive response to mild threat, in that mice lacking 2 subunits exhibited anxious phenotype[20]. The animal models above also have parallel human findings, which we will now mention.

Deficits of GABA neuronal functioning have been implicated in the pathophysiology of PD by recent 1H-MRS[21-23], GABAA-benzodiazepine receptor single photon emission computed tomography (SPECT)[24] and positron emission tomography (PET) studies[25,26]. Not unlike the lactate-sensitive animals referred to earlier, humans with PD have been reported to have cortical GABA deficits in occipital, ACC/medial prefrontal cortex (mPFC), and basal ganglia regions of interest, though one MRS-GABA study of the prefrontal cortex was negative[27] (Table 1 for additional details). Similar GABA deficits (also identified by MRS) have been reported in other human anxiety spectrum disorders, such as social anxiety disorder[28] and obsessive compulsive disorder (OCD) (thalamic and mPFC deficits respectively)[29]. If GABA deficits in humans with PD also extend to impairment of GABAergic inhibition of DMH ORX neurons, this could account for spontaneous or lactate-induced panic in PD patients and in other anxiety patients who experience panic. Other domains of PD symptomatology, such as neophobia, anticipatory fear, and phobic avoidance, could conceivably be more related to the cortical deficits in GABAA receptor status identified by the PET and SPECT investigations above.

Table 1 Neuroimaging studies of gamma amino acid butyric acid function in anxiety disorders.
MethodFindingDesignClinical significanceRef.
123I-Iomazenil SPECTDecreased L hippocampus and precuneus GABAA R bindingParallel gp, 13 PD patients vs 16 healthy control subjects (HCs)Chronic stress due to active PD can result in impaired limbic processing via reduced GABAA receptor density or functionBremner et al[24]
1H-MRSDecreased OC GABA in PD14 PD vs 14 matched HCs (historical)Could be related to impaired production of GABA or of GABA-glutamine cycling in PDGoddard et al[21]
GABA, 1.5TNo change in OC GABA pre and post-acute and chronic BZD Rx10 PD vs 9 HCsSuggests low GABA is a trait-like biomarker for PDGoddard et al[30]
1H-MRS GABA, 3TDecreased ACC and BG GABA in patients22 PD (medicated) vs 24 matched HCs, single voxel studyImpaired top-down inhibition of limbic activity in PDHam et al[23]
11C-flumazenil PETReduced GABAA R binding in L and R insula Cx of PD11 PD vs 21 HCsInteroceptive/somaticsensitivity in PD likely could be insula-mediatedCameron et al[25]
1H-MRS-GABA, 4TReduced thalamic GABA in SAD10 SAD patients vs 10 matched HCsImpaired GABA function in thalamus in SAD could affect social cognition via amplification of external threat cuesPollack et al[28]
11C-flumazenil PETReduced frontal, temporal, parietal Cx GABAA binding pot. in PD15 BZD-naïve PD vs 18 HCsGeneralized cortical impairment in GABAA function in PD could be a cause or effect of PD. If endogenous BZD-like ligands overproduced could be evidence of a compensatory response to chronic stressHasler et al[26]
1H-MRS-GABA, 3TNormal PFC GABA in PDParallel gp 17 PD vs 17 sex-matched HCsIn contrast to previous + results in ACC and OC ROIsHasler et al[27]
1H-MRS-GABA, 3TReduced mPFC GABA in OCD24 OCD patients vs 22 matched HCsCould contribute to cortical-striatal circuit dysfunction in OCDSimpson et al[29]
1H-MRS-GABA, 3TReduced ACC/mPFCx GABA in PDParallel gp 11 PD vs 8 matched HCsEffect size greater in FHx+ PDLong et al[22]
ACC GABA negatively correlated with enhanced ACC-precuneus, connectivity, 2 DMN nodesShin et al[70]
1H-MRS-GABA, 4TLow R Ar insula Cx GABA in PTSD13 PTSD patients vs 13 matched HCsRelationship btw low insula GABA and higher state-trait anxiety levelsRosso et al[50]
1H-MRS-GABA, 4TLower GABA in tempo-parietal Cx and occipital-parietal Cx in PTSD27 PTSD patients vs 18 trauma- exposed controlsLow GABA finding mediated by high levels of insomniaMeyerhoff et al[51]
1H-MRS-GABA, 3TElevated DLPFC and ACC GABA and glutathione levels12 PTSD patients vs 17 non-PTSD trauma controlsOxidative stress implicated in the pathophysiology of PTSD, as well as elevated prefrontal inhibitory neurotransmissionMichel et al[52]

Furthermore, low cortical GABA in PD might be a trait-like entity, since neither acute nor chronic administration of anxiolytic pharmacotherapy was associated with reversal of these deficits[30]. Thus, low cortical GABA could be an important ongoing vulnerability factor conferring panic-proneness[31]. Moreover, in a retrospective analysis of one data set, the presence of a mood or anxiety family history appeared related to the magnitude of cortical GABA deficits observed in PD[32]. Low cortical GABA therefore has potential as a biomarker for PD and related stress conditions.

Human genetics studies of GABA and PD

The familiality and heritability of PD have been well established. Based on a heritability estimate of 43%[33], genetic factors are a significant contributor to the pathogenesis of PD. However, despite extensive clinical investigations in a number of anxiety disorders, the question remains open as to which genes are critically involved in anxiogenesis[34]; this is likely due to the fact that the “genetic architecture” of PD, similar to other high-prevalence medical conditions, is complex and attributable to multiple genes of small effect. The GABA neuronal system, though, continues to be a logical candidate system for future genetic studies of PD because of the current clinical neurobiological data (reviewed above) implicating GABA abnormalities in this condition, as well as the effectiveness of established and promising GABAergic therapies (Table 2).

Table 2 Gamma amino acid system butyric acid effects of psychotropics with anxiolytic activity.
DrugEffect on GABA systemTest paradigmCommentsRef.
BenzodiazepinesAgonists at GABAA receptor complexAlprazolam blocked ACC activation induced by CCK4 in controls.fMRI study in 16 healthy male subjectsLeicht et al[71]
Preclinical study of BZD effects on conditioned and unconditioned fear in miceα2 subunit-containing GABAA receptors sufficient for BZD anxiolysis of unconditioned fear. α1 and α2 subunits needed to suppress conditioned fearSmith et al[72]
SSRIsIncreased cortical GABA levelsClinical MRS-GABA in MDD patientsSanacora et al[73]
Increased neuroactive steroid levels in the CNSCSF ALLO increases in SSRI treated MDD patients (n = 15)Uzunova et al[74]
TCAsIncreased release of GABAPreclinical; desipramine effects studiedKorf et al[75]
MAOIsIncrease total brain GABAPreclinical study of phenelzine effectsPaslawski et al[76]
GabapentinIncreased cortical GABAMRS-GABA in seizure patientsChronic medication adminPetroff et al[77]
PGBIncreased release of GABAPGB decreases activation of left insula and amygdala in response to emotional imagesfMRI activation study in 16 healthy humansAupperle et al[78]
TiagabineBlocks GAT-1 and inhibits synaptic GABA reuptakeFDG-PET study pre and post a 6-week tiagabine trial for social phobia15 social anxiety disorder patients and 10 controls. vmPFC metabolism increased with treatmentEvans K et al[79]
VigabatrinBlocks GABA transaminaseBlocks CCK4 panic in healthy humansNot clinically available due to ocular AEsZwanger et al[80]

Despite the recent positive GABAA receptor PET imaging findings in PD, work evaluating the potential role of GABAA receptor genes (GABRA2, 3, 6, and GABRAG2) in anxiety spectrum disorders has thus far been negative[35]. Other studies have focused on the genes GAD1 and GAD2, which code for the GABA synthetic isoenzymes, GAD67 (found throughout the neuron), and GAD65 (found more in axon terminals, and related to regulation of short-term demands for GABA), respectively. In the investigation of Hettema et al[36] 2006, involving 589 patients and 539 controls, the data suggested an association of several SNPs of the GAD1 gene with the personality trait of neuroticism (N), a risk factor for both anxiety disorders and major depression (MDD). A more recent case-control study, in a cohort of n = 268 anxiety patients, n = 542 MDD patients, and n = 541 healthy subjects, identified an association between elevated levels of behavioral inhibition trait (BI) in the patient groups, and several GAD2 gene SNPs[37]. Finally, an association study in a cohort of n = 238 anxiety patients (84% with PD), and n = 267 healthy subjects recently linked several SNPs (rs2930152, rs2697153, and rs956053) of the GAT1 transporter gene, SLC6A1, with panic attacks. The odds ratio of the association increased in more severely ill patients (frequent panickers), reaching a value of 2.5[38]. However, none of these studies assessed cortical GABA as part their study design. One recent investigation, employing this strategy to explore 5-HT/GABA interactions as a risk factor for panic/anxiety disorder, reported an association between (higher) prefrontal GABA concentrations and presence of a tryptophan hydroxylase isoform 2 gene polymorphism, especially in female mood/anxiety patients. This polymorphism had been previously linked to decreased TPH2 mRNA expression in PD. Follow-up studies are needed to confirm this association due to the small subgroup size of patients studied; however, this line of inquiry is exciting given the high rate of women affected by PD. There is also preliminary evidence of GAD1 gene hypomethylation as a potential epigenetic response to negative life stressors in PD[39]. This is of significance clinically due to the close association of life events and onset of PD illness episodes, and in view of the MRS data suggesting that low cortical GABA is a risk factor for panic-proneness.

GAD/TRAIT ANXIETY AND GABA

Several animal models have linked perturbations in GABA function to elevated trait anxiety. For example, mice bred for high anxiety behaviors (HAB), compared to control animals, were found to have a complex pattern of intra-amygdala GABA neuronal changes[40]. The amygdala has been identified as a key fear-processing structure within the fear circuit. Levels of GAD65 and GAD67 mRNA and protein were elevated in the basolateral amygdala (BLA) in HAB animals vs controls. In addition, mRNA expression of GABAA receptor subunits 1, 2, and 2 in the BLA was increased in HAB mice, while transcription of 5 and 1 subunits was reduced in the central and medial amygdala. Also, BLA levels of FosB, a marker for neuronal activation, were notably increased. This pattern of findings in HAB animals can be interpreted as evidence of excessive excitation in the BLA due to loss of inhibitory GABA tone from the central and medial nuclei, with compensatory upregulation of BLA GABA synthetic enzymes. In another study, liver X receptor knockout mice were noted to exhibit anxious behaviors and to have reduced expression of GAD65 and 67 enzymes in the ventromPFC[41]. Anxiety in this protocol could have been mediated by loss of ventromedial prefrontal inhibitory GABA tone to the amygdala. Chronic anxiety in rodents was induced by inhibition of GABA synthesis in the bed nucleus of the stria terminalis area of the extended amygdala, a model reminiscent of human GAD, since these animals not only had persistent anxiety, but were also lactate-insensitive[42].

Thus far, there have been no clinical studies of cortical GABA levels or GABAA receptor binding in GAD, and, to date, genetic association studies of GABAA receptor subtypes have been negative[35]. Of interest clinically are studies which provide indirect evidence of excessive amygalar excitability in GAD patients. In one fMRI study comparing GAD patients and healthy subjects, neutral and threat cues triggered excessive amygdalar activation responses in GAD subjects[43]. This result is consistent with of an excitation/inhibition imbalance (glutamate/GABA function imbalance) within the amygdala in GAD, and is also consistent with the animal model findings presented above.

PTSD AND GABA FUNCTION
Animal studies

An unpredictable stress paradigm (unpaired odor-shock administration) in neonatal rodents, was associated with anxiety phenotypic behavior in adulthood, together with amygdalar upregulation of genes related to synaptic transmission, such as serotonin (5-HT) and GABA genes[44]. In another rodent study focusing on inescapable stress (inescapable footshock), and examining morphological and neurochemical changes in the prefrontal cortex and hippocampus, post-stress hippocampus cell damage was observed and found to be related to a glutamate/GABA neurochemical imbalance[45]. One group has recently developed a PTSD mouse model by inducing a null mutation in the GAD65 gene. The GAD65 enzyme, as noted previously, is critically involved in activity-dependent regulation of GABA release, and is necessary for proper maturation of the GABA system in adolescence. Mutant mice had hyperexcitability of the amygdala and hippocampus, increased anxiety, and pathological fear memory, all features of human PTSD[46]. In contrast, a GAD65 haplodeficiency animal model was associated with delayed elevations in cortical and limbic GABA levels, yet was found in these animals to confer resilience to the effects of stress[47]. In another animal model of chronic stress (immobilization/restraint stress), tonic (but not phasic) GABAA receptor currents in the amygdala were observed to be persistently reduced following this type of stress, resulting in excessive amygdalar excitability[48]. Such enduring, stress-related changes could be relevant to the development of human anxiety and stress disorders. Furthermore, chronic restraint stress in high-anxiety animals in one study led to decreased brain (cortex and hippocampus) expression of 2 subunits of the GABAA receptor, suggesting a role for these changes in HPA axis dysfunction (upregulation) and stress symptomatology[49].

Several MRS-GABA studies have also documented abnormalities in cortical GABA in human PTSD (Table 1). For example, insula cortex GABA levels in PTSD patients were recently found to be decreased[50]. In another protocol, combat PTSD patients vs non-combat controls exhibited abnormally low levels of parieto-occipital and temporal cortical GABA, which were accounted for by insomnia severity[51]. Yet another group has reported abnormal increases in prefrontal cortical GABA and glutathione in PTSD, implicating oxidative stress and possibly increased frontal cortical inhibition in PTSD pathophysiology[52].

Clinical significance

From the available data it is unclear whether deficits in GABA neurotransmission are a risk factor for PTSD, or are mainly the result of chronic stress, and the associated symptoms of PTSD. It is also unclear whether GABA deficits/dysfunction in PTSD could be the result of compensatory responses to stress that have become depleted, or whether they are particularly involved in the perpetuation of components of chronic PTSD (e.g., hyperarousal, cue-sensitivity, increased startle).

SEPARATION ANXIETY AND GABA

Animal work has implicated the GABA system in unexpected ways in the behavioral and neurochemical response to maternal separation (MS). In one investigation, MS, in addition to promoting anxiety behaviors, enhanced tonic GABA currents in cortical layer 5 pyramidal neurons (juvenile rats), and promoted subsequent neurogenesis (subventricular zone, cortical layer 1, and dentate gyrus), and differentiation into GABA neurons (adult rats)[53]. These persistent brain changes might, in turn, predispose to later-life behavioral disturbances. Some investigators have noted that MS during breast-feeding produced behavioral changes and GABAA receptor 1 subunit expression changes that were gender-dependent[54]. In this study, MS male rats vs controls tended to exhibit less exploratory behavior, and have less 1 subunit expression in the amygdala, mPFC, and paraventricular nucleus (PVN). Females, however, had more exploratory and head-dipping behaviors vs controls, and less subunit staining in the mPFC, PVN, preoptic area, and hippocampus. These results highlight the possibility of gender difference in mechanisms of anxiogenesis. This line of inquiry may well improve our understanding of gender differences in the expression of human anxiety syndromes. A recent review of biological underpinnings of critical periods in fear learning and memory encoding highlighted the potential role of the GABA system on neuroplasticity in the peri-adolescent period. Adolescence is a time when GABA neurotransmission is rapidly improving in efficiency, and disruption in these often nonlinear developmental processes could predispose to anxiety and mood pathology in the adolescence and beyond[55]. To date, there has been little work in humans directly exploring the impact of developmental events/stressors on GABA function, but this could be a fruitful area of investigation.

GABA DEFICITS AND ANXIETY IN OTHER NEUROPSYCHIATRIC DISORDERS

Studies of other pathological conditions with anxiety as a feature [traumatic brain injury (TBI), temporal lobe epilepsy (TLE), and depression (MDD), have also suggested a relationship between impaired GABA function and anxious behavior. Using a rodent model of mild TBI (mild controlled cortical impact), experimenters reported trauma-related increases in anxiety, and reduced BLA GABA function (decreased GABA cell numbers) leading to BLA hyper-excitability[56]. In TLE patients with mood or anxiety syndromes, together with several other GABA system changes, temporal lobe tissue levels of GABA were noted to be lower vs autopsy controls[57]. Finally, in a CSF assessment study of un-medicated MDD patients, those with anxious features tended to have abnormally low CSF GABA levels in contrast to patients without anxious features[58]. Thus, abnormal GABA function could be an important mediator of anxiety across multiple neuropsychiatric syndromes, and these preliminary data suggests the potential efficacy of GABAergic pharmacotherapies to stabilize this symptom cluster (Table 2).

DISCUSSION/TREATMENT IMPLICATIONS

Table 1 summarizes the human neuroimaging studies implicating GABA neuronal dysfunction in anxiety and stress disorders. The majority of the studies, utilizing 1H-MRS techniques, have reported cortical or subcortical GABA deficits in structures relevant to the fear circuit across several different diagnoses. Most studies, however, have been conducted with relatively small samples. The PTSD findings should be interpreted with caution as other factors such as state anxiety, and insomnia appear to be mediating some of the GABA changes reported. In the case of PD, there were 3 positive findings (2 in the ACC/mPFC and 1 in the OC), and one negative finding (prefrontal cortex). One of the ACC studies (Ham et al[23]), however, was conducted in medicated PD patients, and hence it is impossible, in this instance, to attribute the GABA changes to the PD diagnosis. The ability to look at interrelated amino-acid metabolites (GABA, glutamate, glutamine) can add power to a study, as demonstrated in the OCD report of Simpson et al[29] where impaired mPFC GABA inhibition of subcortical structures was associated with elevated glutamate/glutamine levels in the thalamus. The majority of studies provided a baseline GABA assessment, and therefore, while suggestive of an association with a specific disorder, at this stage of the research, the idea that the findings indicated effects of chronic stress cannot be ruled out totally. One exception was one of the PD studies in which acute and chronic benzodiazepine medication effects were prospectively measured, and which suggested loss of normal acute GABA counter-regulatory mechanisms, and tonically low GABA in PD[30]. A limitation of this study was the selection of the OC ROI, which is not directly related to fear-processing circuitry. While there is more consistency with the GABAA receptor findings in PD, again cause-effect relationship cannot readily be disentangled with the study designs used. Future study designs are likely to benefit power-wise from a careful assessment of family history status[32], and the use of a combination of functional imaging techniques (e.g., fMRI or fcMRI together with MRS-GABA assessments), as well as the use of more dynamic MRS approaches (e.g., 13C-labelled glucose/MRS evaluations assessing neuronal and glial contributions to the total GABA pool). The use of more dimensional approaches to anxiety psychopathology classification, as proposed in the NIMH RDoC project, may improve consistency of results (e.g., studying acute responses to fear vs anticipatory fear across a range of DSM-V anxiety conditions). Finally, there are important limitations with the GABA neuroimaging paradigms reviewed. MRS evaluations of GABA offer an integrated assessment of intra-neuronal GABA in a large ROI, while current SPECT and PET methodologies offer the ability to study post-synaptic GABAA receptor status. However, the ability to adapt PET methodology to study the intra-synaptic fraction of GABA, as recently reported[59], now permits a more comprehensive evaluation of GABA neurotransmission across neuropsychiatric disorders.

GABA AND ANXIOLYTIC TREATMENT MECHANISMS

The GABA system has been implicated in the therapeutic mechanism of action of a number of psychotropic agents with anxiolytic activity (Table 2). Benzodiazepine full agonists (BZDs) are the prototypical class of agents in this respect, and their allosteric enhancement effect at the BZD site of GABAA receptor complex is well known[60]. Preclinical work has further defined the role of discrete GABAA receptor subunits in the separate clinical effects of the BZDs such as anxiolysis, sedation, muscle relaxation, and anticonvulsant effects. The 2 subunit for instance, is necessary to the anxiolytic action of BZDs[60]. In contrast, sedative, anticonvulsant, amnestic, and dependency effects in general require the presence of the 1 subunit[61]. Antidepressant agents also have the capacity to facilitate GABA function via augmentation of GABA levels, and neurosteroid levels. Also, newer-generation GABAergic anticonvulsant medications have begun to demonstrate anxiolytic effects, in parallel with localized physiological changes within the fear circuit. From the overview provided in Table 2, enhancement of GABA neurotransmission might be viewed as a final common pathway of anxiolytics in general, or at least a key pathway for anxiolysis. If, as the literature currently suggests, GABA neuronal deficits/abnormalities are present in a range of clinical anxiety conditions, then GABA enhancers of different types might be expected to offset these deficits, thereby promoting anxiolysis, and restoration of function. The future prospect of more predictive and personalized anxiety treatment planning and monitoring is also attainable given the availability of imaging tools that can reliably measure cortical GABA, and other amino-acid metabolites. In the specific case of PD, where cortical GABA level deficits may be trait-like, it would be of interest to know if long-term GABA deficits persist, or whether they resolve at some point during maintenance treatment. “Normalization” of CNS GABA levels might be a more appropriate end point/cue to taper psychotropic treatment when combined with more traditional clinical indices of remission.

NOVEL ANXIOLYTICS TARGETING GABA

The GABA system provides a rich array of molecular targets for ongoing drug development initiatives, offering hope for stress/anxiety conditions in which GABA impairments are implicated. Considerable effort has been devoted to the enterprise of generating non-sedative anxiolytics, based on targeting selective GABAA receptor subunits. While, in this regard, 2/3 subunit-selective compounds have shown much promise in the lab[62], translation to the clinical has been limited by adverse events (e.g., liver toxicity)[63]. More recently, attention has focused on subunit-selective compound development with both preclinical[64] and clinical progress being made[65]. The latter agent, etifoxine, exhibits a dual mechanism, 2/3 subunit selective agonism and neurosteroidogenic stimulation, to enhance GABA neurotransmission. A novel molecular target for ligand development, a mitochondrial Translocator Protein (18 kD), regulates the initial and rate-limiting step in neurosteroidogenesis[66]. Neuroactive steroids synthesized from this pathway, such as allopregnenolone, act as positive allosteric modulators at a specific neurosteroid site within the GABAA receptor complex. Positive synthetic ligands at this site include the agent XBD173, which showed preliminary clinical benefit for panic anxiety, and YL-IPA08, which displayed anxiolysis in a PTSD animal model[67]. In addition, a synthetic neurosteroid analog, ganaxolone, has shown therapeutic potential in a mouse model of PTSD[68]. Within the glutamate system, bilateral intra-amygdala (BLA) administration of the GluK1 kainate receptor agonist ATPA, facilitated GABA neurotransmission to promote anxiolysis in one animal model of stress[69].

CONCLUSION

Anxiety and stress disorders are a major public health concern. However, their pathophysiology is still unclear, and requires ongoing investigation. The GABA neurochemical system has been strongly implicated in their pathogenesis and treatment by numerous preclinical and clinical studies, the most recent of which have been highlighted in this review. Changes in cortical GABA appear related to normal personality styles and normal responses to stress. While there is accumulating in-vivo, neuroimaging evidence of cortical and subcortical GABA deficits across a number of anxiety conditions, a consistent pattern of findings in specific brain regions for a given disorder is yet to emerge. Neuropsychiatric conditions with anxiety as a clinical feature may have GABA deficits as an underlying feature. Different classes of anxiolytic therapies appear to support GABA function, and this may be an area in which newer GABA neuroimaging techniques could soon offer more personalized therapy. Novel GABAergic pharmacotherapies in development offer potential improvements over current therapies in reducing sedative and physiologic dependency effects, while offering rapid anxiolysis.

ACKNOWLEDGMENTS

Many thanks are due to our departmental research manager, Barbara Price, RN, for her contributions to the compilation of this paper.

Footnotes

P- Reviewer: Grof P, Hosak L S- Editor: Qiu S L- Editor: A E- Editor: Jiao XK

References
1.  Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593-602.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11472]  [Cited by in F6Publishing: 11130]  [Article Influence: 585.8]  [Reference Citation Analysis (1)]
2.  Kessler RC, Avenevoli S, Costello EJ, Georgiades K, Green JG, Gruber MJ, He JP, Koretz D, McLaughlin KA, Petukhova M. Prevalence, persistence, and sociodemographic correlates of DSM-IV disorders in the National Comorbidity Survey Replication Adolescent Supplement. Arch Gen Psychiatry. 2012;69:372-380.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 667]  [Cited by in F6Publishing: 675]  [Article Influence: 51.9]  [Reference Citation Analysis (0)]
3.  Angst J. Modern epidemiology of anxiety: Results of the zurich cohort study. Hum Psychopharmacol Clin Exp. 1999;14:S29-S37.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  McEvoy PM, Grove R, Slade T. Epidemiology of anxiety disorders in the Australian general population: findings of the 2007 Australian National Survey of Mental Health and Wellbeing. Aust N Z J Psychiatry. 2011;45:957-967.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 150]  [Cited by in F6Publishing: 150]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
5.  Steel Z, Marnane C, Iranpour C, Chey T, Jackson JW, Patel V, Silove D. The global prevalence of common mental disorders: a systematic review and meta-analysis 1980-2013. Int J Epidemiol. 2014;43:476-493.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1709]  [Cited by in F6Publishing: 1471]  [Article Influence: 147.1]  [Reference Citation Analysis (0)]
6.  Greenberg PE, Sisitsky T, Kessler RC, Finkelstein SN, Berndt ER, Davidson JR, Ballenger JC, Fyer AJ. The economic burden of anxiety disorders in the 1990s. J Clin Psychiatry. 1999;60:427-435.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Heldt SA, Mou L, Ressler KJ. In vivo knockdown of GAD67 in the amygdala disrupts fear extinction and the anxiolytic-like effect of diazepam in mice. Transl Psychiatry. 2012;2:e181.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 53]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
8.  Lange MD, Jüngling K, Paulukat L, Vieler M, Gaburro S, Sosulina L, Blaesse P, Sreepathi HK, Ferraguti F, Pape HC. Glutamic acid decarboxylase 65: a link between GABAergic synaptic plasticity in the lateral amygdala and conditioned fear generalization. Neuropsychopharmacology. 2014;39:2211-2220.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 44]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
9.  Ikeda T, Makino Y, Yamada MK. 17α-estradiol is generated locally in the male rat brain and can regulate GAD65 expression and anxiety. Neuropharmacology. 2015;90:9-14.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 16]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
10.  Kim HJ, Kim JE, Cho G, Song IC, Bae S, Hong SJ, Yoon SJ, Lyoo IK, Kim TS. Associations between anterior cingulate cortex glutamate and gamma-aminobutyric acid concentrations and the harm avoidance temperament. Neurosci Lett. 2009;464:103-107.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 18]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
11.  Goto N, Yoshimura R, Moriya J, Kakeda S, Hayashi K, Ueda N, Ikenouchi-Sugita A, Umene-Nakano W, Oonari N, Korogi Y. Critical examination of a correlation between brain gamma-aminobutyric acid (GABA) concentrations and a personality trait of extroversion in healthy volunteers as measured by a 3 Tesla proton magnetic resonance spectroscopy study. Psychiatry Res. 2010;182:53-57.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 18]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
12.  Hasler G, van der Veen JW, Grillon C, Drevets WC, Shen J. Effect of acute psychological stress on prefrontal GABA concentration determined by proton magnetic resonance spectroscopy. Am J Psychiatry. 2010;167:1226-1231.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 78]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
13.  Streeter CC, Whitfield TH, Owen L, Rein T, Karri SK, Yakhkind A, Perlmutter R, Prescot A, Renshaw PF, Ciraulo DA. Effects of yoga versus walking on mood, anxiety, and brain GABA levels: a randomized controlled MRS study. J Altern Complement Med. 2010;16:1145-1152.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 225]  [Cited by in F6Publishing: 211]  [Article Influence: 15.1]  [Reference Citation Analysis (0)]
14.  Wiebking C, Duncan NW, Tiret B, Hayes DJ, Marjaǹska M, Doyon J, Bajbouj M, Northoff G. GABA in the insula - a predictor of the neural response to interoceptive awareness. Neuroimage. 2014;86:10-18.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 87]  [Cited by in F6Publishing: 88]  [Article Influence: 8.0]  [Reference Citation Analysis (0)]
15.  Lipp I, Evans CJ, Lewis C, Murphy K, Wise RG, Caseras X. The relationship between fearfulness, GABA+, and fear-related BOLD responses in the insula. PLoS One. 2015;10:e0120101.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 14]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
16.  Shekhar A, Keim SR, Simon JR, McBride WJ. Dorsomedial hypothalamic GABA dysfunction produces physiological arousal following sodium lactate infusions. Pharmacol Biochem Behav. 1996;55:249-256.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 81]  [Cited by in F6Publishing: 79]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
17.  Johnson PL, Truitt WA, Fitz SD, Lowry CA, Shekhar A. Neural pathways underlying lactate-induced panic. Neuropsychopharmacology. 2008;33:2093-2107.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 63]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
18.  Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S, Träskman-Bendz L, Goddard AW, Brundin L, Shekhar A. A key role for orexin in panic anxiety. Nat Med. 2010;16:111-115.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 277]  [Cited by in F6Publishing: 298]  [Article Influence: 19.9]  [Reference Citation Analysis (0)]
19.  Crestani F, Lorez M, Baer K, Essrich C, Benke D, Laurent JP, Belzung C, Fritschy JM, Lüscher B, Mohler H. Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci. 1999;2:833-839.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 368]  [Cited by in F6Publishing: 408]  [Article Influence: 16.3]  [Reference Citation Analysis (0)]
20.  Koester C, Rudolph U, Haenggi T, Papilloud A, Fritschy JM, Crestani F. Dissecting the role of diazepam-sensitive γ-aminobutyric acid type A receptors in defensive behavioral reactivity to mild threat. Pharmacol Biochem Behav. 2013;103:541-549.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 14]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
21.  Goddard AW, Mason GF, Almai A, Rothman DL, Behar KL, Petroff OA, Charney DS, Krystal JH. Reductions in occipital cortex GABA levels in panic disorder detected with 1h-magnetic resonance spectroscopy. Arch Gen Psychiatry. 2001;58:556-561.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Long Z, Medlock C, Dzemidzic M, Shin YW, Goddard AW, Dydak U. Decreased GABA levels in anterior cingulate cortex/medial prefrontal cortex in panic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2013;44:131-135.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 69]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
23.  Ham BJ, Sung Y, Kim N, Kim SJ, Kim JE, Kim DJ, Lee JY, Kim JH, Yoon SJ, Lyoo IK. Decreased GABA levels in anterior cingulate and basal ganglia in medicated subjects with panic disorder: a proton magnetic resonance spectroscopy (1H-MRS) study. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:403-411.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 46]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
24.  Bremner JD, Innis RB, White T, Fujita M, Silbersweig D, Goddard AW, Staib L, Stern E, Cappiello A, Woods S. SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry. 2000;47:96-106.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Cameron OG, Huang GC, Nichols T, Koeppe RA, Minoshima S, Rose D, Frey KA. Reduced gamma-aminobutyric acid(A)-benzodiazepine binding sites in insular cortex of individuals with panic disorder. Arch Gen Psychiatry. 2007;64:793-800.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 70]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
26.  Hasler G, Nugent AC, Carlson PJ, Carson RE, Geraci M, Drevets WC. Altered cerebral gamma-aminobutyric acid type A-benzodiazepine receptor binding in panic disorder determined by [11C]flumazenil positron emission tomography. Arch Gen Psychiatry. 2008;65:1166-1175.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 81]  [Cited by in F6Publishing: 84]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
27.  Hasler G, van der Veen JW, Geraci M, Shen J, Pine D, Drevets WC. Prefrontal cortical gamma-aminobutyric Acid levels in panic disorder determined by proton magnetic resonance spectroscopy. Biol Psychiatry. 2009;65:273-275.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 44]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
28.  Pollack MH, Jensen JE, Simon NM, Kaufman RE, Renshaw PF. High-field MRS study of GABA, glutamate and glutamine in social anxiety disorder: response to treatment with levetiracetam. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:739-743.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 78]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
29.  Simpson HB, Shungu DC, Bender J, Mao X, Xu X, Slifstein M, Kegeles LS. Investigation of cortical glutamate-glutamine and γ-aminobutyric acid in obsessive-compulsive disorder by proton magnetic resonance spectroscopy. Neuropsychopharmacology. 2012;37:2684-2692.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 68]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
30.  Goddard AW, Mason GF, Appel M, Rothman DL, Gueorguieva R, Behar KL, Krystal JH. Impaired GABA neuronal response to acute benzodiazepine administration in panic disorder. Am J Psychiatry. 2004;161:2186-2193.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 95]  [Cited by in F6Publishing: 97]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
31.  Gustavsson JP, Pedersen NL, Asberg M, Schalling D. Origins of individual differences in anxiety proneness: a twin/adoption study of the anxiety-related scales from the Karolinska Scales of Personality (KSP). Acta Psychiatr Scand. 1996;93:460-469.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 27]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
32.  Goddard AW, Mason GF, Rothman DL, Behar KL, Petroff OA, Krystal JH. Family psychopathology and magnitude of reductions in occipital cortex GABA levels in panic disorder. Neuropsychopharmacology. 2004;29:639-640.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 10]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
33.  Hettema JM, Neale MC, Kendler KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry. 2001;158:1568-1578.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1007]  [Cited by in F6Publishing: 857]  [Article Influence: 37.3]  [Reference Citation Analysis (0)]
34.  Smoller JW, Block SR, Young MM. Genetics of anxiety disorders: the complex road from DSM to DNA. Depress Anxiety. 2009;26:965-975.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 66]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
35.  Pham X, Sun C, Chen X, van den Oord EJ, Neale MC, Kendler KS, Hettema JM. Association study between GABA receptor genes and anxiety spectrum disorders. Depress Anxiety. 2009;26:998-1003.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 18]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
36.  Hettema JM, An SS, Neale MC, Bukszar J, van den Oord EJ, Kendler KS, Chen X. Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism. Mol Psychiatry. 2006;11:752-762.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 130]  [Cited by in F6Publishing: 136]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
37.  Unschuld PG, Ising M, Specht M, Erhardt A, Ripke S, Heck A, Kloiber S, Straub V, Brueckl T, Müller-Myhsok B. Polymorphisms in the GAD2 gene-region are associated with susceptibility for unipolar depression and with a risk factor for anxiety disorders. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:1100-1109.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 32]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
38.  Thoeringer CK, Ripke S, Unschuld PG, Lucae S, Ising M, Bettecken T, Uhr M, Keck ME, Mueller-Myhsok B, Holsboer F. The GABA transporter 1 (SLC6A1): a novel candidate gene for anxiety disorders. J Neural Transm (Vienna). 2009;116:649-657.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 38]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
39.  Domschke K, Tidow N, Schrempf M, Schwarte K, Klauke B, Reif A, Kersting A, Arolt V, Zwanzger P, Deckert J. Epigenetic signature of panic disorder: a role of glutamate decarboxylase 1 (GAD1) DNA hypomethylation? Prog Neuropsychopharmacol Biol Psychiatry. 2013;46:189-196.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 56]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
40.  Tasan RO, Bukovac A, Peterschmitt YN, Sartori SB, Landgraf R, Singewald N, Sperk G. Altered GABA transmission in a mouse model of increased trait anxiety. Neuroscience. 2011;183:71-80.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 55]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
41.  Tan XJ, Dai YB, Wu WF, Warner M, Gustafsson JÅ. Anxiety in liver X receptor β knockout female mice with loss of glutamic acid decarboxylase in ventromedial prefrontal cortex. Proc Natl Acad Sci USA. 2012;109:7493-7498.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 22]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
42.  Sajdyk T, Johnson P, Fitz S, Shekhar A. Chronic inhibition of GABA synthesis in the bed nucleus of the stria terminalis elicits anxiety-like behavior. J Psychopharmacol. 2008;22:633-641.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 48]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
43.  Nitschke JB, Sarinopoulos I, Oathes DJ, Johnstone T, Whalen PJ, Davidson RJ, Kalin NH. Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response. Am J Psychiatry. 2009;166:302-310.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 243]  [Cited by in F6Publishing: 229]  [Article Influence: 15.3]  [Reference Citation Analysis (0)]
44.  Sarro EC, Sullivan RM, Barr G. Unpredictable neonatal stress enhances adult anxiety and alters amygdala gene expression related to serotonin and GABA. Neuroscience. 2014;258:147-161.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 54]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
45.  Gao J, Wang H, Liu Y, Li YY, Chen C, Liu LM, Wu YM, Li S, Yang C. Glutamate and GABA imbalance promotes neuronal apoptosis in hippocampus after stress. Med Sci Monit. 2014;20:499-512.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 57]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
46.  Müller I, Çalışkan G, Stork O. The GAD65 knock out mouse - a model for GABAergic processes in fear- and stress-induced psychopathology. Genes Brain Behav. 2015;14:37-45.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 41]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
47.  Müller I, Obata K, Richter-Levin G, Stork O. GAD65 haplodeficiency conveys resilience in animal models of stress-induced psychopathology. Front Behav Neurosci. 2014;8:265.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 17]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
48.  Liu ZP, Song C, Wang M, He Y, Xu XB, Pan HQ, Chen WB, Peng WJ, Pan BX. Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents. Mol Brain. 2014;7:32.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 60]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
49.  Wisłowska-Stanek A, Lehner M, Skórzewska A, Krząścik P, Maciejak P, Szyndler J, Ziemba A, Płaźnik A. Changes in the brain expression of alpha-2 subunits of the GABA-A receptor after chronic restraint stress in low- and high-anxiety rats. Behav Brain Res. 2013;253:337-345.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 35]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
50.  Rosso IM, Weiner MR, Crowley DJ, Silveri MM, Rauch SL, Jensen JE. Insula and anterior cingulate GABA levels in posttraumatic stress disorder: preliminary findings using magnetic resonance spectroscopy. Depress Anxiety. 2014;31:115-123.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 73]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
51.  Meyerhoff DJ, Mon A, Metzler T, Neylan TC. Cortical gamma-aminobutyric acid and glutamate in posttraumatic stress disorder and their relationships to self-reported sleep quality. Sleep. 2014;37:893-900.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 100]  [Cited by in F6Publishing: 90]  [Article Influence: 9.0]  [Reference Citation Analysis (0)]
52.  Michels L, Schulte-Vels T, Schick M, O’Gorman RL, Zeffiro T, Hasler G, Mueller-Pfeiffer C. Prefrontal GABA and glutathione imbalance in posttraumatic stress disorder: preliminary findings. Psychiatry Res. 2014;224:288-295.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 65]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
53.  Feng M, Sheng G, Li Z, Wang J, Ren K, Jin X, Jiang K. Postnatal maternal separation enhances tonic GABA current of cortical layer 5 pyramidal neurons in juvenile rats and promotes genesis of GABAergic neurons in neocortical molecular layer and subventricular zone in adult rats. Behav Brain Res. 2014;260:74-82.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 10]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
54.  Leon Rodriguez DA, Duenas Z. Maternal Separation during Breastfeeding Induces Gender-Dependent Changes in Anxiety and the GABA-A Receptor Alpha-Subunit in Adult Wistar Rats. PLoS One. 2013;8:e68010.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 27]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
55.  King EC, Pattwell SS, Glatt CE, Lee FS. Sensitive periods in fear learning and memory. Stress. 2014;17:13-21.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 24]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
56.  Almeida-Suhett CP, Prager EM, Pidoplichko V, Figueiredo TH, Marini AM, Li Z, Eiden LE, Braga MF. Reduced GABAergic inhibition in the basolateral amygdala and the development of anxiety-like behaviors after mild traumatic brain injury. PLoS One. 2014;9:e102627.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 86]  [Article Influence: 8.6]  [Reference Citation Analysis (0)]
57.  Rocha L, Alonso-Vanegas M, Martínez-Juárez IE, Orozco-Suárez S, Escalante-Santiago D, Feria-Romero IA, Zavala-Tecuapetla C, Cisneros-Franco JM, Buentello-García RM, Cienfuegos J. GABAergic alterations in neocortex of patients with pharmacoresistant temporal lobe epilepsy can explain the comorbidity of anxiety and depression: the potential impact of clinical factors. Front Cell Neurosci. 2014;8:442.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
58.  Mann JJ, Oquendo MA, Watson KT, Boldrini M, Malone KM, Ellis SP, Sullivan G, Cooper TB, Xie S, Currier D. Anxiety in major depression and cerebrospinal fluid free gamma-aminobutyric acid. Depress Anxiety. 2014;31:814-821.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 35]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
59.  Stokes PR, Myers JF, Kalk NJ, Watson BJ, Erritzoe D, Wilson SJ, Cunningham VJ, Riano Barros D, Hammers A, Turkheimer FE. Acute increases in synaptic GABA detectable in the living human brain: a [¹¹C]Ro15-4513 PET study. Neuroimage. 2014;99:158-165.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 37]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
60.  Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov. 2011;10:685-697.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 463]  [Cited by in F6Publishing: 498]  [Article Influence: 38.3]  [Reference Citation Analysis (0)]
61.  Heldt SA, Ressler KJ. Amygdala-specific reduction of alpha1-GABAA receptors disrupts the anticonvulsant, locomotor, and sedative, but not anxiolytic, effects of benzodiazepines in mice. J Neurosci. 2010;30:7139-7151.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 31]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
62.  Christian EP, Snyder DH, Song W, Gurley DA, Smolka J, Maier DL, Ding M, Gharahdaghi F, Liu XF, Chopra M. EEG-β/γ spectral power elevation in rat: a translatable biomarker elicited by GABA(Aα2/3)-positive allosteric modulators at nonsedating anxiolytic doses. J Neurophysiol. 2015;113:116-131.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 49]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
63.  Skolnick P. Anxioselective anxiolytics: on a quest for the Holy Grail. Trends Pharmacol Sci. 2012;33:611-620.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 78]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
64.  Yoshimura RF, Tran MB, Hogenkamp DJ, Johnstone TB, Xie JY, Porreca F, Gee KW. Limited central side effects of a β-subunit subtype-selective GABAA receptor allosteric modulator. J Psychopharmacol. 2014;28:472-478.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 9]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
65.  Stein DJ. Etifoxine versus alprazolam for the treatment of adjustment disorder with anxiety: a randomized controlled trial. Adv Ther. 2015;32:57-68.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 39]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
66.  Rupprecht R, Rammes G, Eser D, Baghai TC, Schüle C, Nothdurfter C, Troxler T, Gentsch C, Kalkman HO, Chaperon F. Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science. 2009;325:490-493.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 236]  [Cited by in F6Publishing: 253]  [Article Influence: 16.9]  [Reference Citation Analysis (0)]
67.  Zhang LM, Qiu ZK, Zhao N, Chen HX, Liu YQ, Xu JP, Zhang YZ, Yang RF, Li YF. Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in animal models of post-traumatic stress disorder. Int J Neuropsychopharmacol. 2014;17:1659-1669.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 63]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
68.  Pinna G, Rasmusson AM. Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder. Front Cell Neurosci. 2014;8:256.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 64]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
69.  Masneuf S, Lowery-Gionta E, Colacicco G, Pleil KE, Li C, Crowley N, Flynn S, Holmes A, Kash T. Glutamatergic mechanisms associated with stress-induced amygdala excitability and anxiety-related behavior. Neuropharmacology. 2014;85:190-197.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 48]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
70.  Shin YW, Dzemidzic M, Jo HJ, Long Z, Medlock C, Dydak U, Goddard AW. Increased resting-state functional connectivity between the anterior cingulate cortex and the precuneus in panic disorder: resting-state connectivity in panic disorder. J Affect Disord. 2013;150:1091-1095.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 34]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
71.  Leicht G, Mulert C, Eser D, Sämann PG, Ertl M, Laenger A, Karch S, Pogarell O, Meindl T, Czisch M. Benzodiazepines counteract rostral anterior cingulate cortex activation induced by cholecystokinin-tetrapeptide in humans. Biol Psychiatry. 2013;73:337-344.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 13]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
72.  Smith KS, Engin E, Meloni EG, Rudolph U. Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice. Neuropharmacology. 2012;63:250-258.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 62]  [Cited by in F6Publishing: 67]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
73.  Sanacora G, Mason GF, Rothman DL, Krystal JH. Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry. 2002;159:663-665.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 334]  [Cited by in F6Publishing: 335]  [Article Influence: 15.2]  [Reference Citation Analysis (0)]
74.  Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA. 1998;95:3239-3244.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 495]  [Cited by in F6Publishing: 519]  [Article Influence: 20.0]  [Reference Citation Analysis (0)]
75.  Korf J, Venema K. Desmethylimipramine enhances the release of endogenous GABA and other neurotransmitter amino acids from the rat thalamus. J Neurochem. 1983;40:946-950.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 51]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
76.  Paslawski T, Treit D, Baker GB, George M, Coutts RT. The antidepressant drug phenelzine produces antianxiety effects in the plus-maze and increases in rat brain GABA. Psychopharmacology (Berl). 1996;127:19-24.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  Petroff OA, Rothman DL, Behar KL, Lamoureux D, Mattson RH. The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol. 1996;39:95-99.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 210]  [Cited by in F6Publishing: 220]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
78.  Aupperle RL, Ravindran L, Tankersley D, Flagan T, Stein NR, Simmons AN, Stein MB, Paulus MP. Pregabalin influences insula and amygdala activation during anticipation of emotional images. Neuropsychopharmacology. 2011;36:1466-1477.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 44]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
79.  Evans KC, Simon NM, Dougherty DD, Hoge EA, Worthington JJ, Chow C, Kaufman RE, Gold AL, Fischman AJ, Pollack MH. A PET study of tiagabine treatment implicates ventral medial prefrontal cortex in generalized social anxiety disorder. Neuropsychopharmacology. 2009;34:390-398.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 54]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
80.  Zwanzger P, Baghai TC, Schuele C, Ströhle A, Padberg F, Kathmann N, Schwarz M, Möller HJ, Rupprecht R. Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers. Neuropsychopharmacology. 2001;25:699-703.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 51]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]