Gamma-aminobutyric Acid Neurotransmitter System Research Articles

Neuronal circuits of stress and their dynamic interactions: a biopsychological framework

Stress alters neuroendocrine, autonomic, and behavioral processes to cope well with perceived threats that compromise subjective wellbeing. Just as the perception of risk can change the structure and function of brain circuitry, which may result in enduring behavioral changes. There needs to be a greater understanding of how the brain reacts to stress-related disorders and discern how the adaptation mechanisms of the central nervous system under acute stress, as well as how stressinduced adaptation mechanisms are altered under chronic stress conditions that may induce plasticity-related changes in the brain. During this interaction, the brain becomes more capable of resolving stress in a way that is either adaptive or maladaptive, leaving the most critical deficit in the emotion regulation associated with risk for pathological conditions. The essence of this associated risk involves the reciprocal influence between hypothalamic-pituitary-adrenal function, the relay nucleus within the amygdala reactivation, and the hippocampus as essential structures associated with the forebrain pathways mediating stress-induced hormones, and the gammaaminobutyric acid neurotransmitter system as key mechanisms of regulating stress. Understanding how related emotional experiences occur on the neural level and their impact on cognition and behavior entail tracing the interaction between the hypothalamic-pituitary-adrenal axis, the hormones released by these structures, and the neuroendocrine system's reactivity to stress. The interaction between threat-sensitive brain circuitry and the neuroendocrine stress system is crucial to understanding how related emotions arise on the neural level and their impact on cognition and behavior. The hypothalamicpituitary-adrenal axis is critical in regulating the synthesis and release of endocrine hormones through its interactions with these structures, collectively referred to as the stress response. The stress system is described in its anatomy and physiology and connections to other brain areas and endocrine systems. We explore the current evidence linking stress with pathophysiologic mechanisms implicated in stressful conditions affecting the neuronal circuitry between endocrine, metabolic, gastrointestinal, and immune systems. Examining the biopsychological contributions provides a conceptual framework for understanding the emergence of emotions and stress-related behaviors.

Characterization of the GABAergic system in Asian clam Corbicula fluminea: Phylogenetic analysis, tissue distribution, and response to the aquatic contaminant carbamazepine

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter involved in the neuro-endocrine-immune (NEI) system. In this study, we sequenced the partial length of cDNA fragments of three genes involved in GABA neurotransmitter system of the Asian clam (Corbicula fluminea) (GABAA receptor-associated protein (GABARAP), GABARAPL2 and GABA transporter (GAT-1)). These genes exhibited high amino acid sequence identity compared with other invertebrate orthologs. Expression patterns of the three genes were determined in mantle, gill, gonad, digestive gland and muscle, and the steady state levels of mRNA for each were determined to be highest in gonad and lowest in muscle. To determine their regulation by pharmaceuticals that are present as contaminants in waterways, clams were exposed to carbamazepine (CBZ) for 30 days. CBZ is an agonist for GABA receptors and is an anticonvulsant pharmaceutical that is often detected in aquatic ecosystems. GABARAP and GABARAPL2 mRNA levels were significantly downregulated by 5 and 50 μg/L CBZ in mantle and gill (p < 0.05), while in the gonad and digestive gland, steady state levels (p < 0.05) were decreased with exposure to all three doses. GAT-1 mRNA was upregulated by CBZ (p < 0.05) in the mantle and gill at all three doses tested and in the gonad and digestive system with 5 and 50 μg/L. These data suggest that CBZ disrupt the expression of the GABAergic neurotransmitter system in C. fluminea. Moreover, GABARAP, GABARAPL2 and GAT-1 may be useful biomarkers for the screening of substances that are hazardous to the NEI system of mollusks.

Tributyltin enhanced anxiety of adult male zebrafish through elevating cortisol level and disruption in serotonin, dopamine and gamma-aminobutyric acid neurotransmitter pathways

Tributyltin (TBT), a widely and persistently distributed organontin, has been well documented to disrupt reproduction and behaviors in animals due to its anti-aromatase activity. TBT has been also reported to enhance anxiety in several fish species, whereas the mechanism underlying remains largely unknown. To investigate the disruption of TBT on fish anxiety and the mechanisms possibly involved, adult male zebrafish (Danio rerio) were treated with TBT (100 and 500 ng/L) for 28 days and anxiety behavior was further investigated using a novel tank dive test. Result showed that TBT treatment significantly enhanced the total time of the fish spent in the lower half, delayed the onset time to the higher half of the tank and increased the total duration of freezing of the fish, indicating an enhanced anxiety in TBT-treated fish. Accordingly, TBT sharply elevated the cortisol levels in plasma in a concentration-dependent manner, suggesting that the elevated cortisol level might be involved in the enhanced anxiety. Although the expression of crha was significantly increased and crhbp was significantly decreased in the brain of TBT-treated fish which is consistent to the elevated cortisol level, the expressions of actha and acthb were sharply down-regulated. In contrast, the expressions of genes responsible for the synthesis and action of serotonin (5-HT) (pet1, thp2 and htr1aa), dopamine (DA) (th1, slc6a3, drd2a and drd2b) and gamma-aminobutyric acid (GABA) (gad2 and gabrg2) were all significantly inhibited. The down-regulation of these pivotal genes acting in 5-HT, DA and GABA neurotransmitter systems in response to TBT corresponded well with the TBT-enhanced anxiety in fish. It was thus strongly suggested that these neurotransmitters might be also involved in TBT-enhanced anxiety in adult male zebrafish. The present study extended our understanding of the neurotoxicity of TBT on the anxiety control and behavioral modulation in fish.

The recognition and management of protracted alcohol withdrawal may improve and modulate the pharmacological treatment of alcohol use disorder.

About 50% of persons with an alcohol use disorder may have symptoms of alcohol withdrawal syndrome (AWS) when they reduce or discontinue their alcohol consumption. Protracted alcohol withdrawal (PAW), an underestimated and not yet clearly defined clinical condition that follows the acute stage of AWS, is characterized by the presence of substance-specific signs and symptoms (i.e. anxiety, irritability, mood instability, insomnia, craving) common to acute AWS, but persisting beyond the generally expected acute AWS time frames. Considering that PAW symptoms are mainly related to the neuro-adaptive changes of gamma-aminobutyric acid (GABA) and N-methyl-d-aspartate (NMDA) systems, naltrexone, nalmefene, and disulfiram may not be able to suppress the symptoms of PAW. After treatment of the acute phase of AWS, a more specifically pharmacological therapy able to suppress PAW symptoms could perhaps be used earlier and may be more helpful in preventing the risk of alcohol relapse, which remains higher during the first months of treatment. In light of this, medications acting on GABA and NMDA neurotransmitter systems to counterbalance the up-regulation of NMDA and the down-regulation of GABA could be employed in combination and started as soon as possible.

Ketamine, Esketamine, and A New Generation of Antidepressants

Since the discovery of its rapid-acting antidepressant properties, ketamine has helped stimulate a new line of research in the development of rapid-acting antidepressants based on the glutamate and gamma-aminobutyric acid neurotransmitter systems. An intranasal version of the S-enantiomer of ketamine (esketamine) recently received regulatory approval as a therapy for treatment-resistant depression (TRD). Here we review the clinical evidence of esketamine for TRD, challenges to its adoption in clinical practice, and the regulatory requirements imposed by the US Food and Drug Administration (FDA) through a risk evaluation and mitigation strategy (REMS). Brexanolone, an exogenous formulation of allopregnanolone, also recently received FDA approval for the treatment of postpartum depression and is likewise subject to a REMS. Other compounds in late-stage development, including AXS-05 and SAGE-217, are also reviewed. [ Psychiatr Ann . 2020;50(2):54–61.]

Special Issue: Integrating Mindfulness Training with Clinical Biofeedback: Practical Applications

This special issue continues the focus of the spring and summer 2018 issues (Volume 46, Issues 1 and 2) on the benefits of integrating mindfulness and biofeedback approaches and identifies several new areas of application in pediatric biofeedback, the treatment of adults with intellectual disabilities, care for persons with respiratory illness and mechanical ventilation, and the management of chronic multiple sclerosis.The issue opens with an article by two leaders in biofeedback, who argue that mindfulness is as a natural extension of the awareness training inherent in biofeedback and other self-regulation approaches. Eric Peper and Richard Harvey compare mindfulness with other self-regulation strategies, such as progressive muscle relaxation, autogenic training, and transcendental meditation. They identify common elements shared by mindfulness with other self-regulation strategies. They also argue that most of the commonly used self-regulation strategies have comparable efficacy. They suggest mechanisms making many such self-regulation skills effective, including effects on the gamma aminobutyric acid neurotransmitter system. Finally, they call for further research to explore dropout rates, adverse effects, and other dimensions of mindfulness training.Next, Jonathan Sikorski and Olivia Hernandez-Gonzalez address the challenges in applying mindfulness-based interventions with two special populations. They point out that young children often struggle with communicating their needs, feelings, and desires with others. Adults with intellectual disabilities face similar challenges. The authors introduce practical strategies they have developed to introduce mindfulness skills for these two groups. They also use biofeedback as a tool to assist both groups in enhancing internal awareness of the link between emotions and physiological sensations. To illustrate their approach, they present two case narratives, the first a 10-year-old boy with generalized anxiety disorder, and the second a 28-year-old adult with Prader-Willi syndrome and intellectual disabilities.Urszula Klich presents a case study illustrating her clinical approach, which emphasizes teaching self-regulation and compassion. The case example in her article presents a patient with a tracheostomy who is experiencing anxiety related to pain and anxiety about eventual removal of her vent. Mechanical ventilation for acute respiratory insufficiency accounts for approximately 800,000 hospitalizations each year, and discontinuation of mechanical ventilation is challenging for patients and care teams alike. Klich combined compassion-based strategies with biofeedback to reduce anxiety about decannulation (removal of the tracheostomy tube). Her interventions included mindfulness meditation, breath training, heart rate variability training, loving kindness meditation, and the use of mindfulness strategies to ameliorate anxiety.In the final article, Donald Moss discusses the integration of mindfulness training, clinical biofeedback, and lifestyle change in the management of multiple sclerosis (MS). Moss provides a discussion of the medical diagnosis and treatment of MS, a review of the epidemiology and genetics of the condition, and a case narrative describing a 36-year-old woman with a pattern of chronic relapsing MS. This chapter also shows the use of the Pathways Model to organize treatment. The Pathways Model is an overall self-directed program of acquiring self-regulation skills and implementing lifestyle changes as a supplement to professional intervention.

Small RNA regulation of neural gene expression in response to environmental exposure associated with neuropsychiatric syndromes

Postmortem molecular analysis of the human brain during development and aging suggests there are epigenetic changes reflecting early life experiences. This includes changes in the expression of non-coding RNAs such as microRNA. These molecules alter the regulation of gene expression and can interact with underlying genetic risk factors, contributing to neurological and neuropsychiatric syndromes such as schizophrenia. Recent evidence suggests that these dynamic and influential molecules play an important role in both brain development and the cellular response to stress. In our recent studies, we investigate the role of microRNA in the brains’ response to maternal immune activation and adolescent cannabinoid exposure, alone and in combination, as both have been identified as environmental risk factors for this disorder. We found that combined exposure to significantly altered microRNA expression in the left hemisphere of the entorhinal cortex as compared to the right. These changes were dominated by a large subgroup of microRNA transcribed from a single imprinted locus on chromosome 6q32 that is associated with schizophrenia. These changes correlated with altered gene expression in the combined treatment group, with microRNA-gene interactions predicted to regulate neuronal growth and differentiation; development of specific cortical layers; synaptic plasticity and transmission; axonogenesis; gamma-aminobutyric acid neurotransmitter system; and learning and memory formation. These findings suggested that the interaction of both an early and late environmental insult enhances changes in offspring microRNA expression in the brain with possible outcomes relevant to neurological disorders in adulthood.

A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder

Gamma-amino butyric acid (GABA) and glutamate are the major inhibitory and excitatory neurotransmitters in the mammalian central nervous system, respectively, and have been associated with suicidal behavior and major depressive disorder (MDD). We examined the relationship between genotype, brain transcriptome, and MDD/suicide for 24 genes involved in GABAergic and glutamatergic signaling. In part 1 of the study, 119 candidate SNPs in 24 genes (4 transporters, 4 enzymes, and 16 receptors) were tested for associations with MDD and suicidal behavior in 276 live participants (86 nonfatal suicide attempters with MDD and 190 non-attempters of whom 70% had MDD) and 209 postmortem cases (121 suicide deaths of whom 62% had MDD and 88 sudden death from other causes of whom 11% had MDD) using logistic regression adjusting for sex and age. In part 2, RNA-seq was used to assay isoform-level expression in dorsolateral prefrontal cortex of 59 postmortem samples (21 with MDD and suicide, 9 MDD without suicide, and 29 sudden death non-suicides and no psychiatric illness) using robust regression adjusting for sex, age, and RIN score. In part 3, SNPs with subthreshold (uncorrected) significance levels below 0.05 for an association with suicidal behavior and/or MDD in part 1 were tested for eQTL effects in prefrontal cortex using the Brain eQTL Almanac (www.braineac.org). No SNPs or transcripts were significant after adjustment for multiple comparisons. However, a protein coding transcript (ENST00000414552) of the GABA A receptor, gamma 2 (GABRG2) had lower brain expression postmortem in suicide (P = 0.01) and evidence for association with suicide death (P = 0.03) in a SNP that may be an eQTL in prefrontal cortex (rs424740, P = 0.02). These preliminary results implicate GABRG2 in suicide and warrant further investigation and replication in larger samples.

Effects of tetrahydropalmatine on post-traumatic stress disorder-induced changes in rat brain gene expression

The aim of this research proposal was to investigate the effects of tetrahydropalmatine (THP) on gene expression in a post-traumatic stress disorder (PTSD) rodent model. Eighty male Sprague-Dawley rats were randomly assigned to the nonstressed groups or the 3-day restraint shock PTSD rodent model groups. There were four groups within the nonstressed rats (control, THP, midazolam, and midazolam with THP) and four groups within the stressed rats (control, THP, midazolam, and midazolam with THP). After injection the subjects were euthanized and the amygdala and hippocampus were sent for reverse transcriptase-polymerase chain reaction gene expression analysis. Of the genes interrogated, 17 genes in the amygdala and 18 genes in the hippocampus were found to have significant changes in gene expression and regulation. Significant transcriptional fold changes were found in important genes involved in dopamine, serotonin, acetylcholine, and gamma-aminobutyric acid neurotransmitter systems. The results provide quantifiable data demonstrating gene expression changes in PTSD-stressed and nonstressed rats receiving various treatments. These findings contribute important data to the limited molecular details pertaining to the neurobiology of PTSD.

Emerging approaches to managing alcohol dependence

To review pharmacotherapies and psychosocial interventions for the treatment of alcohol dependence, including recent developments that may minimize nonadherence. Alcohol dependence is a widespread, chronic disorder with enormous health consequences. Psychological and behavioral therapies have been the mainstay of treatment and are demonstrated to be effective, but they do not lead to reduced drinking or abstinence in all patients. Advances in neurobiology have led to the identification of drug targets and the development of novel drugs to treat alcohol dependence, and many patients will benefit from the addition of pharmacotherapy to their treatment regimen. Pharmacologic treatment options for use in conjunction with psychotherapy include the aversion-based therapy disulfiram, the opioid receptor antagonist naltrexone, and acamprosate, which is thought to act by normalizing the glutamate and gamma-aminobutyric acid neurotransmitter systems. The effectiveness of pharmacotherapies depends on adherence, which is often poor in alcohol-dependent patients. Recently, a monthly, extended-release formulation of naltrexone has been approved for alcohol dependence, which promises to minimize nonadherence, a problematic factor in the management of alcohol dependence. Pharmacotherapy added to psychosocial therapy can improve treatment effectiveness. Advances in drug delivery mechanisms, such as injectable and extended-release formulations, may improve medication adherence rates in patients with alcohol dependence, thereby enhancing patient outcomes.

Action of 4-amino-2-fluorobutanoic acid and other structural analogues on gamma-aminobutyric acid transport by channel catfish brain.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in mammalian brain. The synaptic action of GABA is terminated by a sodium- and chloride-linked transport system. The GABA transporter is known as GAT and several isoforms have been identified. Many components of a GABA neurotransmitter system, including a GABA transport system, are present in channel catfish brain. Using a synaptosomal preparation of catfish brain, we examined the kinetics of inhibition of GABA transport by 4-amino-2-fluorobutanoic acid and several other structural analogues of GABA. The transport constant (Kt) for GABA uptake was 4.46 microM, and 4-amino-2-fluorobutanoic acid produced a noncompetitive type of inhibition (Ki = 12.5 microM). The most potent inhibitors were tiagabine (Ki = 0.23 microM) and (R,S)nipecotic acid (Ki = 2.2 microM), both of which exhibited competitive inhibition. Like 4-amino-2-fluorobutanoic acid, homo-beta-proline (Ki = 9.4 microM) inhibited noncompetitively. Other analogues exhibited competitive inhibition. These observations suggest that the GABA transport system in channel catfish is remarkably similar to that in mammalian brain.

Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy.

There appears to be a consensus that hepatic encephalopathy (HE) is a metabolic encephalopathy with a multifactorial pathogenesis. One of the factors considered to be important in the pathogenesis of HE is ammonia. However, the mechanisms by which ammonia contributes to the manifestations of HE remain poorly defined. Ammonia could be more definitively implicated in the pathogenesis of HE if its effects can be shown to lead to an enhancement of inhibitory neurotransmission. In this context the effects of ammonia on the GABA (gamma-aminobutyric acid) neurotransmitter system may be relevant. Ammonia, at the modestly increased concentrations that commonly occur in precoma HE (0.15 mM-0.75 mM), has been shown to increase GABA-induced chloride current in cultured neurons, probably by modifying the affinity of the GABA(A) receptor for GABA. Comparable ammonia concentrations also enhanced synergistically the binding of a GABA agonist and a benzodiazepine (BZ) agonist to the GABA(A) receptor complex, phenomena which would enhance the neuroinhibitory effects of these ligands. Also, GABA increased the potency of ammonia-induced enhancement of the binding of a BZ agonist to the GABA(A) receptor complex, and brain levels of BZ agonists are elevated in liver failure. In addition, ammonia has been shown to inhibit astrocytic uptake of GABA by 30%-50%, an effect which would increase the synaptic availability of GABA at GABA(A) receptors. Furthermore, increased ammonia concentrations upregulate the peripheral-type benzodiazepine receptor in the outer membrane of astroglial mitochondria, thereby enhancing astrocytic mitochondrial synthesis and release of neurosteroids. Some neurosteroids, for example tetrahydroprogesterone (THP) and tetrahydrodeoxycorticosterone (THDOC), are potent agonists of the GABA(A) receptor complex, on which there are specific binding sites for neurosteroids, that are distinct from those for BZs and barbiturates. Tetrahydroprogesterone and tetrahydrodeoxycorticosterone levels were found to be increased in a mouse model of acute liver failure, and, when THP or THDOC was injected into normal mice, sedation and Alzheimer type II astrocytic changes in the cortex, striatum, and hypothalmus were induced. Each of these direct or indirect effects of ammonia on the GABA neurotransmitter system has the potential of increasing inhibitory neurotransmission, and, hence, contributing to the manifestations of HE.

Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy.

Several lines of emerging evidence suggest that dysfunction of gamma-aminobutyric acid (GABA) systems is associated with major depression. However, investigation of this hypothesis is limited by difficulty obtaining noninvasive in vivo measures of brain GABA levels. In this study we used in vivo proton magnetic resonance spectroscopy to investigate the hypothesis that abnormalities in the GABA neurotransmitter system are associated with the neurobiologic processes of depression. The GABA levels were measured in the occipital cortex of medication-free depressed patients meeting DSM-IV criteria (n = 14) and healthy control subjects with no history of mental illness (n = 18) using a localized difference editing proton magnetic resonance spectroscopy protocol. An analysis of covariance was employed to examine the effects of depression, sex, and age. The depressed patients demonstrated a highly significant (52%) reduction in occipital cortex GABA levels compared with the group of healthy subjects. While there were significant age and sex effects, there was no interaction of diagnosis with either age or sex. This study provides the first evidence of abnormally low cortical GABA concentrations in the brains of depressed patients.

Association between the GABAA receptor ?5 subunit gene locus (GABRA5) and bipolar affective disorder

Genetic factors seem to play an important role in the pathogenesis of affective disorder. The candidate gene strategies are being used, among others, to identify the genes conferring vulnerability to the disease. The genes coding for the receptors of gamma-aminobutyric acid (GABA) have been proposed as candidates for affective disorder, since the GABA neurotransmitter system has been implicated in the pathogenesis of the illness. We examined the possible genetic association between the GABA(A) receptor alpha5 subunit gene locus (GABRA5) on chromosome 15 and affective disorder, in 48 bipolar patients (BP), 40 unipolar patients (UP), and 50 healthy individuals, age- and sex-matched to the patients. All patients and controls were unrelated Greeks. Diagnoses were made after direct interviews according to the DSM-IV and ICD-10 criteria. For the genotyping, a dinucleotide (CA) repeat marker was used. The polymerase chain reaction (PCR) products found were nine alleles with lengths between 272 and 290 base pairs (bp). The distribution of allelic frequencies of the GABRA5 locus differed significantly between BP patients and controls with the 282-bp allele found to be associated with BP affective disorder, while no such difference was observed between the groups of UP patients and controls nor between the two patient groups. The presence or absence of the 282-bp allele in the genotype of BP patients was not shown to influence the age of onset and the overall clinical severity, but was found to be associated with a preponderance of manic over depressive episodes in the course of the illness.

The GABA hypothesis--state of the art.

Before the gamma-aminobutyric acid (GABA) hypothesis was proposed more than a decade ago there had been increasing awareness that the hypotheses of the pathogenesis of hepatic encephalopathy (HE) then in vogue did not adequately account for all of the manifestations of this syndrome. A particular deficiency of those hypotheses was their failure to account for the manifestations of the syndrome in terms of abnormal neural mechanisms (1). Although GABA had been included in lists of substances that had been considered in relation to HE (2), the possibility of an involvement of the GABA neurotransmitter system in its pathogenesis had not been seriously assessed.

The γ-Aminobutyric Acid A (GABAA) Receptor Complex and Hepatic Encephalopathy

Increased neural inhibition appears to be an important component of the syndrome of hepatic encephalopathy. The pathways subserved by the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex are the principal inhibitory systems in the mammalian brain. Hyperpolarization of neural membranes is accomplished by an increase in transmembrane chloride flux through a GABA-gated chloride channel in the complex. The opening of the chloride channel is induced by the binding of GABA to its receptors, and it is potentiated by barbiturates or benzodiazepines that act at distinct recognition sites on the complex. Involvement of the GABA neurotransmitter system in hepatic encephalopathy is suggested by several findings in animal models of fulminant hepatic failure. For example, hepatic encephalopathy resembles encephalopathies induced by drugs (including benzodiazepines) that potentiate GABAergic neurotransmission. In addition, neurons from animals with hepatic encephalopathy show increased sensitivity to benzodiazepine and GABA receptor agonists. Moreover, these neurons are excited by benzodiazepine receptor antagonists at concentrations that do not affect control neurons. Also, elevated levels of a substance that inhibits radioligand binding to benzodiazepine receptors have been found in cerebrospinal fluid from animals with hepatic encephalopathy. Furthermore, manifestations of hepatic encephalopathy can be ameliorated by benzodiazepine receptor antagonists. The relevance of these findings to hepatic encephalopathy in human beings is supported by clinical observations showing that a benzodiazepine receptor antagonist can lessen the degree of hepatic encephalopathy. These findings suggest that an endogenous substance with benzodiazepine-like properties contributes to the neuropsychiatric manifestations of hepatic encephalopathy by augmenting GABAergic neurotransmission.