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EPA Science Inventory

The project studies the inhibitory effect of lead on the enzymatic activity of brain glutamic amino acid decarboxylase (GADC). The enzyme is responsible for the catalytic formation of gamma amino butyric acid (GABA) inhibitory neurons which is believed to be involved with the tra...


?-Amino-butyric acid (GABA) receptor subunit and transporter expression in the gonad and liver of the fathead minnow (Pimephales promelas).  


?-Amino-butyric acid (GABA) is the major inhibitory neurotransmitter in the vertebrate central nervous system. GABA receptors and synthesizing enzymes have also been localized to peripheral tissues including the liver, oviduct, uterus and ovary of mammals but the distribution and role of GABA in peripheral tissues of fish has not been fully investigated. The objectives of this study were to (1) determine if mRNA encoding GABA synthesizing enzymes (glutamic acid decarboxylase 65 and 67; gad65 and gad67), GABA transporters, and GABAA receptor subunits are localized to liver and gonad of fathead minnow (Pimephales promelas) (FHM) (2) investigate the effects of GABA on ovarian 17?-estradiol (E2) production, and (3) measure transcript responses in the ovary after in vitro incubation to GABA. Real-time PCR assays were developed for gad65, gad67, vesicular GABA transporter (vgat) and GABA transporter 1 (gat1), and select GABAA receptor subunits (gabra1, gabra5, gabrb1, gabrb2, gabrg1, gabrg2). All transcripts were localized to the brain as expected; however transcripts were also detected in the liver, ovary, and testis of FHMs. In the female liver, gad65 mRNA was significantly higher in expression compared to the male liver. Transcripts for gad67 were the highest in the brain>gonad>liver and in the gonads, gad67 was significantly higher in expression than gad65 mRNA. In the liver and gonad, the relative abundance of the subunits followed a general trend of gabrb1>gabrb2=gabrg1=gabrg2>gabra1=gabra5. To explore the effects of GABA in the ovary, tissue explants from reproductive female FHMs were treated with GABA (10(-10), 10(-8) and 10(-6)M) for 12h. GABA had no significant effect on 17?-estradiol production or on mRNA abundance for genes involved in ovarian steroidogenesis (e.g., 11?hsd, cyp17, cyp19a). There was a significant decrease in estrogen receptor 2a (esr2a) mRNA with 10(-10)M GABA. This study begins to investigate the GABA system in non-neural tissues of teleost fish and addresses the broader topic regarding the peripheral roles of neurotransmitters. PMID:23672824

Biggs, Katie; Seidel, Jason S; Wilson, Alex; Martyniuk, Christopher J



Optimization of ?-amino butyric acid production in a newly isolated Lactobacillus brevis.  


An isolate from kimchi, identified as Lactobacillus brevis, accumulated ?-aminobutyric acid (GABA), a major inhibitory neurotransmitter, in the culture medium. Optimal culture conditions for growth of L. brevis and production of GABA were 6 % (w/v) l-glutamic acid, 4 % (w/v) maltose, 2 % (w/v) yeast extract, 1 % (w/v) NaCl, 1 % (w/v) CaCl2, 2 g Tween 80/l, and 0.02 mM pyridoxal 5?-phosphate at initial pH 5.25 and 37 °C. GABA reached 44.4 g/l after 72 h cultivation with a conversion rate 99.7 %, based on the amount (6 %) of l-glutamic acid added. GABA was purified using ion exchange column chromatography with 70 % recovery and 97 % purity. PMID:24078124

Binh, Tran Thi Thanh; Ju, Wan-Taek; Jung, Woo-Jin; Park, Ro-Dong



Cardiac sympathetic afferent reflex response to intermedin microinjection into paraventricular nucleus is mediated by nitric oxide and ?-amino butyric acid in hypertensive rats.  


Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide (CGRP) and involves in the regulation of cardiovascular function in both peripheral tissues and central nervous system (CNS). Paraventricular nucleus (PVN) of hypothalamus is an important site in the control of cardiac sympathetic afferent reflex (CSAR) which participates in sympathetic over-excitation of hypertension. The aim of this study is to investigate whether IMD in the PVN is involved in the inhibition of CSAR and its related mechanism in hypertension. Rats were subjected to two-kidney one-clip (2K1C) surgery to induce renovascular hypertension or sham-operation (Sham). Acute experiments were carried out four weeks later under anesthesia. The CSAR was evaluated with the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to the epicardial application of capsaicin. The RSNA and MAP were recorded in sinoaortic-denervated, cervical-vagotomized and anesthetized rats. Bilateral PVN microinjection of IMD (25?pmol) caused greater decrease in the CSAR in 2K1C rats than in Sham rats, which was prevented by pretreatment with adrenomedullin (AM) receptor antagonist AM22-52, non-selective nitric oxide (NO) synthase (NOS) inhibitor L-NAME or ?-amino butyric acid (GABA)B receptor blocker CGP-35348. PVN pretreatment with CGRP receptor antagonist CGRP8-37 or GABA(A) receptor blocker gabazine had no significant effect on the CSAR response to IMD. AM22-52, L-NAME and CGP-35348 in the PVN could increase CSAR in Sham and 2K1C rats. These data indicate that IMD in the PVN inhibits CSAR via AM receptor, and both NO and GABA in the PVN involve in the effect of IMD on CSAR in Sham and renovascular hypertensive rats. PMID:24872434

Zhou, Hong; Sun, Hai-jian; Chang, Jin-rui; Ding, Lei; Gao, Qing; Tang, Chao-shu; Zhu, Guo-qing; Zhou, Ye-bo



LeProT1, a transporter for proline, glycine betaine, and gamma-amino butyric acid in tomato pollen.  

PubMed Central

During maturation, pollen undergoes a period of dehydration accompanied by the accumulation of compatible solutes. Solute import across the pollen plasma membrane, which occurs via proteinaceous transporters, is required to support pollen development and also for subsequent germination and pollen tube growth. Analysis of the free amino acid composition of various tissues in tomato revealed that the proline content in flowers was 60 times higher than in any other organ analyzed. Within the floral organs, proline was confined predominantly to pollen, where it represented >70% of total free amino acids. Uptake experiments demonstrated that mature as well as germinated pollen rapidly take up proline. To identify proline transporters in tomato pollen, we isolated genes homologous to Arabidopsis proline transporters. LeProT1 was specifically expressed both in mature and germinating pollen, as demonstrated by RNA in situ hybridization. Expression in a yeast mutant demonstrated that LeProT1 transports proline and gamma-amino butyric acid with low affinity and glycine betaine with high affinity. Direct uptake and competition studies demonstrate that LeProT1 constitutes a general transporter for compatible solutes. PMID:10072398

Schwacke, R; Grallath, S; Breitkreuz, K E; Stransky, E; Stransky, H; Frommer, W B; Rentsch, D



Mutations in ?-aminobutyric acid (GABA) transaminase genes in plants or Pseudomonas syringae reduce bacterial virulence  

Microsoft Academic Search

Pseudomonas syringae pv. tomato DC3000 is a bacterial pathogen of Arabidopsis and tomato that grows in the apoplast. The non-protein amino acid ?-amino butyric acid (GABA) is produced by Arabidopsis and tomato and is the most abundant amino acid in the apoplastic fluid of tomato. The DC3000 genome harbors three genes annotated as gabT GABA transaminases. A DC3000 mutant lacking

Duck Hwan Park; Rossana Mirabella; Philip A. Bronstein; Gail M. Preston; Michel A. Haring; Chun Keun Lim; Alan Collmer; Robert C. Schuurink



Upregulation of genes related to bone formation by ?-amino butyric acid and ?-oryzanol in germinated brown rice is via the activation of GABAB-receptors and reduction of serum IL-6 in rats  

PubMed Central

Background Osteoporosis and other bone degenerative diseases are among the most challenging non-communicable diseases to treat. Previous works relate bone loss due to osteoporosis with oxidative stress generated by free radicals and inflammatory cytokines. Alternative therapy to hormone replacement has been an area of interest to researchers for almost three decades due to hormone therapy-associated side effects. Methods In this study, we investigated the effects of gamma-amino butyric acid (GABA), gamma-oryzanol (ORZ), acylated steryl glucosides (ASG), and phenolic extracts from germinated brown rice (GBR) on the expression of genes related to bone metabolism, such as bone morphogenic protein-2 (BMP-2), secreted protein acidic and rich in cysteine (SPARC), runt-related transcription factor 2 (RUNX-2), osteoblast-specific transcription factor osterix (Osx), periostin, osteoblast specific factor (Postn), collagen 1&2 (Col1&2), calcitonin receptor gene (CGRP); body weight measurement and also serum interleukin-6 (IL-6) and osteocalcin, in serum and bone. Rats were treated with GBR, ORZ, GABA, and ASG at (100 and 200 mg/kg); estrogen (0.2 mg/kg), or remifemin (10 and 20 mg/kg), compared to ovariectomized non-treated group as well as non-ovariectomized non-treated (sham) group. Enzyme-linked immunosorbent assay was used to measure the IL-6 and osteocalcin levels at week 2, 4, and 8, while the gene expression in the bone tissue was determined using the Genetic Analysis System (Beckman Coulter Inc., Brea, CA, USA). Results The results indicate that groups treated with GABA (100 and 200 mg/kg) showed significant upregulation of SPARC, calcitonin receptor, and BMP-2 genes (P < 0.05), while the ORZ-treated group (100 and 200 mg/kg) revealed significant (P < 0.05) upregulation of Osx, Postn, RUNX-2, and Col1&2. Similarly, IL-6 concentration decreased, while osteocalcin levels increased significantly (P < 0.05) in the treated groups as compared to ovariectomized non-treated groups. Conclusion GABA and ORZ from GBR stimulates osteoblastogenesis by upregulation of bone formation genes, possibly via the activation of GABAB receptors and by inhibiting the activity of inflammatory cytokines and reactive oxygen species. Therefore, it could be used effectively in the management of osteoporosis. PMID:24098073

Muhammad, Sani Ismaila; Maznah, Ismail; Mahmud, Rozi; Zuki, Abu Bakar Zakaria; Imam, Mustapha Umar



Mapping convulsants' binding to the GABA-A receptor chloride ionophore: A proposed model for channel binding sites  

E-print Network

Abstract Gamma-aminobutyric acid (GABA) type A receptors play a key role in brain inhibitory neurotransmission, and are ligand-activated chloride channels blocked by numerous convulsant ligands. Here we and GABA-A receptor complex Gamma-amino butyric acid (GABA) is the primary mediator of inhibitory

Kalueff, Allan V.


Pollen Tube Growth and Guidance Is Regulated by POP2, an Arabidopsis Gene that Controls GABA Levels  

Microsoft Academic Search

During angiosperm reproduction, pollen grains form a tube that navigates through female tissues to the micropyle, delivering sperm to the egg; the signals that mediate this process are poorly understood. Here, we describe a role for ?-amino butyric acid (GABA) in pollen tube growth and guidance. In vitro, GABA stimulates pollen tube growth, although vast excesses are inhibitory. The Arabidopsis

Ravishankar Palanivelu; Laura Brass; Anna F. Edlund; Daphne Preuss



Mutations in ?-aminobutyric acid (GABA) transaminase genes in plants or Pseudomonas syringae reduce bacterial virulence.  


Pseudomonas syringae pv. tomato DC3000 is a bacterial pathogen of Arabidopsis and tomato that grows in the apoplast. The non-protein amino acid ?-amino butyric acid (GABA) is produced by Arabidopsis and tomato and is the most abundant amino acid in the apoplastic fluid of tomato. The DC3000 genome harbors three genes annotated as gabT GABA transaminases. A DC3000 mutant lacking all three gabT genes was constructed and found to be unable to utilize GABA as a sole carbon and nitrogen source. In complete minimal media supplemented with GABA, the mutant grew less well than wild-type DC3000 and showed strongly reduced expression of hrpL and avrPto, which encode an alternative sigma factor and effector, respectively, associated with the type III secretion system. The growth of the gabT triple mutant was weakly reduced in Arabidopsis ecotype Landberg erecta (Ler) and strongly reduced in the Ler pop2-1 GABA transaminase-deficient mutant that accumulates higher levels of GABA. Much of the ability to grow on GABA-amended minimal media or in Arabidopsis pop2-1 leaves could be restored to the gabT triple mutant by expression in trans of just gabT2. The ability of DC3000 to elicit the hypersensitive response (HR) in tobacco leaves is dependent upon deployment of the type III secretion system, and the gabT triple mutant was less able than wild-type DC3000 to elicit this HR when bacteria were infiltrated along with GABA at levels of 1 mm or more. GABA may have multiple effects on P. syringae-plant interactions, with elevated levels increasing disease resistance. PMID:21070411

Park, Duck Hwan; Mirabella, Rossana; Bronstein, Philip A; Preston, Gail M; Haring, Michel A; Lim, Chun Keun; Collmer, Alan; Schuurink, Robert C



Distribution of GABA-like immunoreactive neurons in the slug Limax maximus  

Microsoft Academic Search

Immunohistochemical techniques were used to study the distribution of gamma-amino butyric acid (GABA)-like immunoreactive neurons in the nervous system of the slug Limax maximus. Approximately 170 GABA-like immunoreactive cell bodies were found in the central nervous system. These were located in the cerebral, buccal and pedal ganglia. Most GABA-like immunoreactive neurons had small cell bodies, which were aggregated into discrete

Ian R. C. Cooke; Alan Gelperin



Induction of the GABA Cell Phenotype: An In Vitro Model for Studying Neurodevelopmental Disorders  

Microsoft Academic Search

Recent studies of the hippocampus have suggested that a network of genes is associated with the regulation of the GAD67 (GAD1) expression and may play a role in ?-amino butyric acid (GABA) dysfunction in schizophrenia (SZ) and bipolar disorder (BD). To obtain a more detailed understanding of how GAD67 regulation may result in GABAergic dysfunction, we have developed an in

Sivan Subburaju; Francine M. Benes



GABAA receptor needs two homologous domains of the & beta;-subunit for activation by GABA but not by pentobarbital  

Microsoft Academic Search

THE predominant inhibitory neurotrasmitter of the brain, GABA (gamma-amino butyric acid), activates chloride-selective ion pores integral to the receptor complex. Subunits comprising the pre-sumed hetero-pentameric GABA channel have been cloned1-4, but little information is available on the domains important for activation. Rat wild-type or mutated alpha1-, & beta;2- and gamma2-subunits (designated alpha, beta and gamma) were coexpressed in Xenopus oocytes

Jahanshah Amin; David S. Weiss



BAT1, a bidirectional amino acid transporter in Arabidopsis  

Microsoft Academic Search

The Arabidopsis thaliana At2g01170 gene is annotated as a putative gamma amino butyric acid (GABA) permease based on its sequence similarity to a\\u000a yeast GABA transporting gene (UGA4). A cDNA of At2g01170 was expressed in yeast and analyzed for amino acid transport activity. Both direct measurement of amino\\u000a acid transport and yeast growth experiments demonstrated that the At2g01170 encoded-protein exhibits

Ekrem Dündar; Daniel R. Bush



Distribution of GABA-like immunoreactive neurons in the slug Limax maximus.  


Immunohistochemical techniques were used to study the distribution of gamma-amino butyric acid (GABA)-like immunoreactive neurons in the nervous system of the slug Limax maximus. Approximately 170 GABA-like immunoreactive cell bodies were found in the central nervous system. These were located in the cerebral, buccal and pedal ganglia. Most GABA-like immunoreactive neurons had small cell bodies, which were aggregated into discrete clusters within the cerebral and pedal ganglia. Three pairs of longer, uniquely identifiable, GABA-like immunoreactive cells were found in the cerebral ganglion. GABA-like immunoreactive nerve fibres were also found in all of the central ganglia but were absent from peripheral nerves. These results suggest that GABA acts as a central neurotransmitter in the slug. The possible roles of GABA-ergic neurotransmission in the slug are discussed. PMID:2458189

Cooke, I R; Gelperin, A



Glutaminase catalyzes reaction of glutamate to GABA.  


Here, for the first time, we report an NMR spectroscopy study of l-Glutamine (Gln) conversion by Glutaminase (Glnase), which shows that the reaction involves two distinct steps. In the first step, Glnase rapidly hydrolyzes Gln to Glutamate (Glu) (?16.87 ?mol of Gln/min/mg of Glnase) and in the second step, Glu generated in the first step is decarboxylated into gamma-amino butyric acid (GABA) with a much slower rate (?0.185 ?mol/min/mg). When Glnase was added to the sample containing l-Glu alone, it was also converted to GABA, at a similar rate as in the second step mentioned above. The rate of Glu decarboxylation into GABA by Glnase is about an order of magnitude lower than that by commonly known enzyme, Glutamate decarboxylase. Potential impact of these findings, on the mechanistic aspects of Gln-Glu shuttle in neuroscience and glutaminolysis in tumors, is discussed. PMID:24755074

Nanga, Ravi Prakash Reddy; DeBrosse, Catherine; Singh, Anup; D'Aquilla, Kevin; Hariharan, Hari; Reddy, Ravinder



Fast detection of extrasynaptic GABA with a whole-cell sniffer  

PubMed Central

Gamma-amino-butyric acid (GABA) is the main inhibitory transmitter of the brain. It operates by binding to specific receptors located both inside and outside synapses. The extrasynaptic receptors are activated by spillover from GABAergic synapses and by ambient GABA in the extracellular space. Ambient GABA is essential for adjusting the excitability of neurons. However, due to the lack of suitable methods, little is known about its dynamics. Here we describe a new technique that allows detection of GABA transients and measurement of the steady state GABA concentration with high spatial and temporal resolution. We used a human embryonic kidney (HEK) cell line that stably expresses GABAA receptors composed of ?1, ?2, and ?2 subunits. We recorded from such a HEK cell with the whole-cell patch-clamp technique. The presence of GABA near the HEK cell generated a measurable electric current whose magnitude increased with concentration. A fraction of the current did not inactivate during prolonged exposition to GABA. This technique, which we refer to as a “sniffer” allows the measurement of ambient GABA concentration inside nervous tissue with a resolution of few tens of nanomolars. In addition, the sniffer detects variations in the extrasynaptic GABA concentration with millisecond time resolution. Pilot experiments demonstrate that the sniffer is able to report spillover of GABA induced by synaptic activation in real time. This is the first report on a GABA sensor that combines the ability to detect fast transients and to measure steady concentrations. PMID:24860433

Christensen, Rasmus K.; Petersen, Anders V.; Schmitt, Nicole; Perrier, Jean-Francois



Collaborative Regulation of Escherichia coli Glutamate-Dependent Acid Resistance by Two AraC-Like Regulators, GadX and GadW (YhiW)  

Microsoft Academic Search

An important feature of Escherichia coli pathogenesis is an ability to withstand extremely acidic environ- ments of pH 2 or lower. This acid resistance property contributes to the low infectious dose of pathogenic E. coli species. One very efficient E. coli acid resistance system encompasses two isoforms of glutamate decarboxylase (gadA and gadB) and a putative glutamate:-amino butyric acid (GABA)

Zhuo Ma; Hope Richard; Don L. Tucker; Tyrrell Conway; John W. Foster



Effect of ?-Aminobutyric Acid (GABA) Producing Bacteria on In vitro Rumen Fermentation, Biogenic Amine Production and Anti-oxidation Using Corn Meal as Substrate  

PubMed Central

The effects and significance of ?-amino butyric acid (GABA) producing bacteria (GPB) on in vitro rumen fermentation and reduction of biogenic amines (histamine, methylamine, ethylamine, and tyramine) using corn meal as a substrate were determined. Ruminal samples collected from ruminally fistulated Holstein cows served as inoculum and corn was used as substrate at 2% dry matter (DM). Different inclusion rates of GPB and GABA were evaluated. After incubation, addition of GPB had no significant effect on in vitro fermentation pH and total gas production, but significantly increased the ammonia nitrogen (NH3-N) concentration and reduced the total biogenic amines production (p<0.05). Furthermore, antioxidation activity was improved as indicated by the significantly higher concentration of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) among treated samples when compared to the control (p<0.05). Additionally, 0.2% GPB was established as the optimum inclusion level. Taken together, these results suggest the potential of utilizing GPB as feed additives to improve growth performance in ruminants by reducing biogenic amines and increasing anti-oxidation. PMID:25049853

Ku, Bum Seung; Mamuad, Lovelia L.; Kim, Seon-Ho; Jeong, Chang Dae; Soriano, Alvin P.; Lee, Ho-Il; Nam, Ki-Chang; Ha, Jong K.; Lee, Sang Suk



Allosteric modulation of retinal GABA receptors by ascorbic acid  

PubMed Central

Summary Ionotropic ?-aminobutyric acid receptors (GABAA and GABAC) belong to the cys-loop receptor family of ligand-gated ion channels. GABAC receptors are highly expressed in the retina, mainly localized at the axon terminals of bipolar cells. Ascorbic acid, an endogenous redox agent, modulates the function of diverse proteins, and basal levels of ascorbic acid in the retina are very high. However, the effect of ascorbic acid on retinal GABA receptors has not been studied. Here we show that the function of GABAC and GABAA receptors is regulated by ascorbic acid. Patch-clamp recordings from bipolar cell terminals in goldfish retinal slices revealed that GABAC receptor-mediated currents activated by tonic background levels of extracellular GABA, and GABAC currents elicited by local GABA puffs, are both significantly enhanced by ascorbic acid. In addition, a significant rundown of GABA-puff evoked currents was observed in the absence of ascorbic acid. GABA-evoked Cl- currents mediated by homomeric ?1 GABAC receptors expressed in Xenopus laevis oocytes were also potentiated by ascorbic acid in a concentration-dependent, stereospecific, reversible, and voltage-independent manner. Studies involving the chemical modification of sulfhydryl groups showed that the two cys-loop cysteines and histidine 141, all located in the ?1 subunit extracellular domain, each play a key role in the modulation of GABAC receptors by ascorbic acid. Additionally, we show that retinal GABAA IPSCs and heterologously expressed GABAA receptor currents are similarly augmented by ascorbic acid. Our results suggest that ascorbic acid may act as an endogenous agent capable of potentiating GABAergic neurotransmission in the CNS. PMID:21715633

Calero, Cecilia I.; Vickers, Evan; Moraga Cid, Gustavo; Aguayo, Luis G.; von Gersdorff, Henrique; Calvo, Daniel J.



Mutation of the Drosophila vesicular GABA transporter disrupts visual figure detection  

PubMed Central

The role of gamma amino butyric acid (GABA) release and inhibitory neurotransmission in regulating most behaviors remains unclear. The vesicular GABA transporter (VGAT) is required for the storage of GABA in synaptic vesicles and provides a potentially useful probe for inhibitory circuits. However, specific pharmacologic agents for VGAT are not available, and VGAT knockout mice are embryonically lethal, thus precluding behavioral studies. We have identified the Drosophila ortholog of the vesicular GABA transporter gene (which we refer to as dVGAT), immunocytologically mapped dVGAT protein expression in the larva and adult and characterized a dVGATminos mutant allele. dVGAT is embryonically lethal and we do not detect residual dVGAT expression, suggesting that it is either a strong hypomorph or a null. To investigate the function of VGAT and GABA signaling in adult visual flight behavior, we have selectively rescued the dVGAT mutant during development. We show that reduced GABA release does not compromise the active optomotor control of wide-field pattern motion. Conversely, reduced dVGAT expression disrupts normal object tracking and figure–ground discrimination. These results demonstrate that visual behaviors are segregated by the level of GABA signaling in flies, and more generally establish dVGAT as a model to study the contribution of GABA release to other complex behaviors. PMID:20435823

Fei, Hao; Chow, Dawnis M.; Chen, Audrey; Romero-Calderón, Rafael; Ong, Wei S.; Ackerson, Larry C.; Maidment, Nigel T.; Simpson, Julie H.; Frye, Mark A.; Krantz, David E.



Characteristics of gamma-aminobutyric acid (GABA) receptors in the rat central nervous system.  


Characteristics of gamma-aminobutyric acid (GABA) were investigated in the rat central nervous system by radioreceptor assay (RRA). Scatchard analysis revealed that the rat brain had two distinct GABA binding sites with an apparent dissociation constant (Kd) of 11.7 nM and 34.7 nM. The highest level of specific [3H]-GABA binding was found in the rat cerebellum. Imidazole acetic acid, a potent GABA agonist, was effective in displacing [3H]-GABA binding but beta-alanine was slightly effective in inhibiting [3H]-GABA binding. Muscimol, the most potent GABA agonist, has been used as a ligand to characterize the postsynaptic GABA receptors. However, the maximal binding capacity (Bmax) of muscimol-RRA was about 3 times larger than that of GABA-RRA, suggesting that muscimol might label not only GABA receptors but other unknown receptors as well. An endogenous inhibitor of GABA receptor binding was purified from the P2 fraction of rat brain with 0.05% Triton X-100. The endogenous inhibitor was competitive with GABA on GABA binding sites. The inhibition by the endogenous inhibitor of GABA receptor binding was blocked by the allosteric effect of diazepam. In the presence of diazepam, [3H]-GABA binding with the endogenous inhibitor was larger than that with GABA, whereas there was no difference in the absence of diazepam. This indicated that the endogenous inhibitor was not GABA itself. The molecular weight of the endogenous inhibitor was estimate by gel filtration to be less than 3,000 daltons. PMID:6307002

Kuroda, H



[Influence of exogenous gamma-aminobutyric acid (GABA) on GABA metabolism and amino acid contents in roots of melon seedling under hypoxia stress].  


This paper investigated the influence of gamma-aminobutyric acid (GABA) on GABA metabolism and amino acid content under hypoxia stress by accurately controlling the level of dissolved oxygen in hydroponics, using the roots of melon 'Xiyu 1' seedlings as the test material. The results showed that compared with the control, the growth of roots was inhibited seriously under hypoxia stress. Meanwhile, the hypoxia-treated roots had significantly higher activities of glutamate decarboxylase (GAD), glutamate dehydrogenase (GDH), glutamate synthase (GOGAT), glutamine synthetase (GS), alanine aminotransferase (ALT), aspartate aminotransferase (AST) as well as the contents of GABA, pyruvic acid, alanine (Ala) and aspartic acid (Asp). But the contents of glutamic acid (Glu) and alpha-keto glutaric acid in roots under hypoxia stress was obviously lower than those of the control. Exogenous treatment with GABA alleviated the inhibition effect of hypoxia stress on root growth, which was accompanied by an increase in the contents of endogenous GABA, Glu, alpha-keto glutaric acid and Asp. Furthermore, under hypoxia stress, the activities of GAD, GDH, GOGAT, GS, ALT, AST as well as the contents of pyruvic acid and Ala significantly decreased in roots treated with GABA. However, adding GABA and viny-gamma-aminobutyric acid (VGB) reduced the alleviation effect of GABA on melon seedlings under hypoxia stress. The results suggested that absorption of GABA by roots could alleviate the injury of hypoxia stress to melon seedlings. This meant that GABA treatment allows the normal physiological metabolism under hypoxia by inhibiting the GAD activity through feedback and maintaining higher Glu content as well as the bal- ance of carbon and nitrogen. PMID:25345052

Wang, Chun-Yan; Li, Jing-Rui; Xia, Qing-Ping; Wu, Xiao-Lei; Gao, Hong-Bo



Genetic manipulation of the ?-aminobutyric acid (GABA) shunt in rice: overexpression of truncated glutamate decarboxylase (GAD2) and knockdown of ?-aminobutyric acid transaminase (GABA-T) lead to sustained and high levels of GABA accumulation in rice kernels.  


Gamma-aminobutyric acid (GABA) is a non-protein amino acid commonly present in all organisms. Because cellular levels of GABA in plants are mainly regulated by synthesis (glutamate decarboxylase, GAD) and catabolism (GABA-transaminase, GABA-T), we attempted seed-specific manipulation of the GABA shunt to achieve stable GABA accumulation in rice. A truncated GAD2 sequence, one of five GAD genes, controlled by the glutelin (GluB-1) or rice embryo globulin promoters (REG) and GABA-T-based trigger sequences in RNA interference (RNAi) cassettes controlled by one of these promoters as well, was introduced into rice (cv. Koshihikari) to establish stable transgenic lines under herbicide selection using pyriminobac. T? and T? generations of rice lines displayed high GABA concentrations (2-100 mg/100 g grain). In analyses of two selected lines from the T? generation, there was a strong correlation between GABA level and the expression of truncated GAD2, whereas the inhibitory effect of GABA-T expression was relatively weak. In these two lines both with two T-DNA copies, their starch, amylose, and protein levels were slightly lower than non-transformed cv. Koshihikari. Free amino acid analysis of mature kernels of these lines demonstrated elevated levels of GABA (75-350 mg/100 g polished rice) and also high levels of several amino acids, such as Ala, Ser, and Val. Because these lines of seeds could sustain their GABA content after harvest (up to 6 months), the strategy in this study could lead to the accumulation GABA and for these to be sustained in the edible parts. PMID:23421475

Shimajiri, Yasuka; Oonishi, Takayuki; Ozaki, Kae; Kainou, Kumiko; Akama, Kazuhito



GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop  

Microsoft Academic Search

Gamma-aminobutyric acid (GABA) is synthesized by two isoforms of the pyridoxal 5?-phosphate–dependent enzyme glutamic acid decarboxylase (GAD65 and GAD67). GAD67 is constitutively active and is responsible for basal GABA production. In contrast, GAD65, an autoantigen in type I diabetes, is transiently activated in response to the demand for extra GABA in neurotransmission, and cycles between an active holo form and

Gustavo Fenalti; Ruby H P Law; Ashley M Buckle; Christopher Langendorf; Kellie Tuck; Carlos J Rosado; Noel G Faux; Khalid Mahmood; Christiane S Hampe; J Paul Banga; Matthew Wilce; Jason Schmidberger; Jamie Rossjohn; Ossama El-Kabbani; Robert N Pike; A Ian Smith; Ian R Mackay; Merrill J Rowley; James C Whisstock



Selected Gamma Aminobutyric Acid (GABA) Esters may Provide Analgesia for Some Central Pain Conditions  

PubMed Central

Central pain is an enigmatic, intractable condition, related to destruction of thalamic areas, resulting in likely loss of inhibitory synaptic transmission mediated by GABA. It is proposed that treatment of central pain, a localized process, may be treated by GABA supplementation, like Parkinson’s disease and depression. At physiologic pH, GABA exists as a zwitterion that is poorly permeable to the blood brain barrier (BBB). Because the pH of the cerebral spinal fluid (CSF) is acidic relative to the plasma, ion trapping may allow a GABA ester prodrug to accumulate and be hydrolyzed within the CSF. Previous investigations with ester local anesthetics may be applicable to some GABA esters since they are weak bases, hydrolyzed by esterases and cross the BBB. Potential non-toxic GABA esters are discussed. Many GABA esters were investigated in the 1980s and it is hoped that this paper may spark renewed interest in their development. PMID:20703328

Goldberg, Joel S.



Selected Gamma Aminobutyric Acid (GABA) Esters may Provide Analgesia for Some Central Pain Conditions.  


Central pain is an enigmatic, intractable condition, related to destruction of thalamic areas, resulting in likely loss of inhibitory synaptic transmission mediated by GABA. It is proposed that treatment of central pain, a localized process, may be treated by GABA supplementation, like Parkinson's disease and depression. At physiologic pH, GABA exists as a zwitterion that is poorly permeable to the blood brain barrier (BBB). Because the pH of the cerebral spinal fluid (CSF) is acidic relative to the plasma, ion trapping may allow a GABA ester prodrug to accumulate and be hydrolyzed within the CSF. Previous investigations with ester local anesthetics may be applicable to some GABA esters since they are weak bases, hydrolyzed by esterases and cross the BBB. Potential non-toxic GABA esters are discussed. Many GABA esters were investigated in the 1980s and it is hoped that this paper may spark renewed interest in their development. PMID:20703328

Goldberg, Joel S



Thyroid hormone and gamma-aminobutyric acid (GABA) interactions in neuroendocrine systems.  


Thyroid hormones (THs) have critical roles in brain development and normal brain function in vertebrates. Clinical evidence suggests that some human nervous disorders involving GABA(gamma-aminobutyric acid)-ergic systems are related to thyroid dysfunction (i.e. hyperthyroidism or hypothyroidism). There is experimental evidence from in vivo and in vitro studies on rats and mice indicating that THs have effects on multiple components of the GABA system. These include effects on enzyme activities responsible for synthesis and degradation of GABA, levels of glutamate and GABA, GABA release and reuptake, and GABA(A) receptor expression and function. In developing brain, hypothyroidism generally decreases enzyme activities and GABA levels whereas in adult brain, hypothyroidism generally increases enzyme activities and GABA levels. Hyperthyroidism does not always have the opposite effect. In vitro studies on adult brain have shown that THs enhance GABA release and inhibit GABA-reuptake by rapid, extranuclear actions, suggesting that presence of THs in the synapse could prolong the action of GABA after release. There are conflicting results on effects of long term changes in TH levels on GABA reuptake. Increasing and decreasing circulating TH levels experimentally in vivo alter density of GABA(A) receptor-binding sites for GABA and benzodiazepines in brain, but results vary from study to study, which may reflect important regional differences in the brain. There is substantial evidence that THs also have an extranuclear effect to inhibit GABA-stimulated Cl(-) currents by a non-competitive mechanism in vitro. The thyroid gland exhibits GABA transport mechanisms as well as enzyme activities for GABA synthesis and degradation, all of which are sensitive to thyroidal state. In rats and humans, GABA inhibits thyroid stimulating hormone (TSH) release from the pituitary, possibly by action directly on the pituitary or on hypothalamic thyrotropin-releasing hormone neurons. In mice, GABA inhibits TSH-stimulated TH release from the thyroid gland. Taken together, these studies provide strong support for the hypothesis that there is reciprocal regulation of the thyroid and GABA systems in vertebrates. PMID:16527506

Wiens, Susanna C; Trudeau, Vance L



[Decreased occipital GABA concentrations in patients with first-episode major depressive disorder: a magnetic resonance spectroscopy study].  


Gamma amino butyric acid (GABA) is the major inhibitory neurotransmitter in the human brain. Alterations in GABAergic function are associated with a variety of neurological and psychiatric disorders. However, noninvasive in vivo measurement of GABA is difficult because of its low concentration and the presence of overlapping resonances. To study GABA concentration in the occipital cortex in major depressive disorder (MDD), a group of medication-naive, first episode depressed patients (n = 18, HAMD > 17), and a group of healthy controls (n = 23) were investigated using a Point Resolved Spectroscopy (MEGA-PRESS) on a 3.0 T MR scanner. The results showed that occipital GABA levels were significantly lower (P < 0.001) in the patient group than those in the healthy controls, yet the correlations between the severity of MDD (HAMD, BDI) and the GABA concentration is insignificant. Therefore, our data suggest that patients with first episode, unmedicated MDD have changes in cortical concentrations of GABA. This biochemical abnormality may be a marker of a trait vulnerability to mood disorder, and may explain the visual problem of severe MDD patients. PMID:22616164

Song, Zhe; Huang, Peiyu; Qiu, Lihua; Wu, Qizhu; Gong, Qiyong; Zhang, Bida; Heberlein, Keith; Xie, Peng



Valerenic acid potentiates and inhibits GABA(A) receptors: molecular mechanism and subunit specificity.  


Valerian is a commonly used herbal medicinal product for the treatment of anxiety and insomnia. Here we report the stimulation of chloride currents through GABA(A) receptors (I(GABA)) by valerenic acid (VA), a constituent of Valerian. To analyse the molecular basis of VA action, we expressed GABA(A) receptors with 13 different subunit compositions in Xenopus oocytes and measured I(GABA) using the two-microelectrode voltage-clamp technique. We report a subtype-dependent stimulation of I(GABA) by VA. Only channels incorporating beta(2) or beta(3) subunits were stimulated by VA. Replacing beta(2/3) by beta(1) drastically reduced the sensitivity of the resulting GABA(A) channels. The stimulatory effect of VA on alpha(1)beta(2) receptors was substantially reduced by the point mutation beta(2N265S) (known to inhibit loreclezole action). Mutating the corresponding residue of beta(1) (beta(1S290N)) induced VA sensitivity in alpha(1)beta(1S290N) comparable to alpha(1)beta(2) receptors. Modulation of I(GABA) was not significantly dependent on incorporation of alpha(1), alpha(2), alpha(3) or alpha(5) subunits. VA displayed a significantly lower efficiency on channels incorporating alpha(4) subunits. I(GABA) modulation by VA was not gamma subunit dependent and not inhibited by flumazenil (1 microM). VA shifted the GABA concentration-effect curve towards lower GABA concentrations and elicited substantial currents through GABA(A) channels at > or = 30 microM. At higher concentrations (> or = 100 microM), VA and acetoxy-VA inhibit I(GABA). A possible open channel block mechanism is discussed. In summary, VA was identified as a subunit specific allosteric modulator of GABA(A) receptors that is likely to interact with the loreclezole binding pocket. PMID:17585957

Khom, S; Baburin, I; Timin, E; Hohaus, A; Trauner, G; Kopp, B; Hering, S



A fluorescence-coupled assay for gamma aminobutyric acid (GABA) reveals metabolic stress-induced modulation of GABA content in neuroendocrine cancer.  


Pathways involved in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA) have been implicated in the pathogenesis of high grade neuroendocrine (NE) neoplasms as well as neoplasms from a non-NE lineage. Using The Cancer Genome Atlas, overexpression of the GABA synthetic enzyme, glutamate decarboxylase 1 (GAD1), was found to be associated with decreased disease free-survival in prostate adenocarcinoma and decreased overall survival in clear cell renal cell carcinomas. Furthermore, GAD1 was found to be expressed in castrate-resistant prostate cancer cell lines, but not androgen-responsive cell lines. Using a novel fluorescence-coupled enzymatic microplate assay for GABA mediated through reduction of resazurin in a prostate neuroendocrine carcinoma (PNEC) cell line, acid microenvironment-induced stress increased GABA levels while alkaline microenvironment-induced stress decreased GABA through modulation of GAD1 and glutamine synthetase (GLUL) activities. Moreover, glutamine but not glucose deprivation decreased GABA through modulation of GLUL. Consistent with evidence in prokaryotic and eukaryotic organisms that GABA synthesis mediated through GAD1 may play a crucial role in surviving stress, GABA may be an important mediator of stress survival in neoplasms. These findings identify GABA synthesis and metabolism as a potentially important pathway for regulating cancer cell stress response as well as a potential target for therapeutic strategies. PMID:24551133

Ippolito, Joseph E; Piwnica-Worms, David



GABA transport and neuroinflammation are coupled in multiple sclerosis: regulation of the GABA transporter-2 by ganaxolone.  


Interactions between neurotransmitters and the immune system represent new prospects for understanding neuroinflammation and associated neurological disease. GABA is the chief inhibitory neurotransmitter but its actions on immune pathways in the brain are unclear. In the present study, we investigated GABAergic transport in conjunction with neuroinflammation in models of multiple sclerosis (MS). Protein and mRNA levels of ?-amino butyric acid transporter 2 (GAT-2) were examined in cerebral white matter from MS and control (Non-MS) patients, in cultured human macrophages, microglia and astrocytes, and in spinal cords from mice with and without experimental autoimmune encephalomyelitis (EAE) using western blotting, immunocytochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). GABA levels were measured by HPLC. The GAT-2's expression was increased in MS patients' (n=6) white matter, particularly in macrophage lineage cells, compared to Non-MS patients (n=6) (p<0.05). Interferon-? (IFN-?) stimulation of human macrophage lineage cells induced GAT-2 expression and reduced extracellular GABA levels (p<0.05) but soluble GABA treatment suppressed HLA-DR?, GAT-2 and XBP-1/s expression in stimulated macrophage lineage cells (p<0.05). Similarly, the synthetic allopregnanolone analog, ganaxolone (GNX), repressed GAT-2, JAK-1 and STAT-1 expression in activated macrophage lineage cells (p<0.05). In vivo GNX treatment reduced Gat-2, Cd3?, MhcII, and Xbp-1/s expression in spinal cords following EAE induction (p<0.05), which was correlated with improved neurobehavioral outcomes and reduced neuroinflammation, demyelination and axonal injury. These findings highlight altered GABAergic transport through GAT-2 induction during neuroinflammation. GABA transport and neuroinflammation are closely coupled but regulated by GNX, pointing to GABAergic pathways as therapeutic targets in neuroinflammatory diseases. PMID:24814730

Paul, A M; Branton, W G; Walsh, J G; Polyak, M J; Lu, J-Q; Baker, G B; Power, C



-Aminobutyric Acid (GABA) and Pentobarbital Induce Different Conformational Rearrangements in the GABAA  

E-print Network

-Aminobutyric Acid (GABA) and Pentobarbital Induce Different Conformational Rearrangements with channel gat- ing. At high concentrations, the barbiturate pentobarbital opens GABAAR channels with similar the structural rearrange- ments induced by barbiturates. Here, we examined whether pentobarbital activation

Kemnitz, Joseph


Induction of the GABA Cell Phenotype: An In Vitro Model for Studying Neurodevelopmental Disorders  

PubMed Central

Recent studies of the hippocampus have suggested that a network of genes is associated with the regulation of the GAD67 (GAD1) expression and may play a role in ?-amino butyric acid (GABA) dysfunction in schizophrenia (SZ) and bipolar disorder (BD). To obtain a more detailed understanding of how GAD67 regulation may result in GABAergic dysfunction, we have developed an in vitro model in which GABA cells are differentiated from the hippocampal precursor cell line, HiB5. Growth factors, such as PDGF, and BDNF, regulate the GABA phenotype by inducing the expression of GAD67 and stimulating the growth of cellular processes, many with growth cones that form appositions with the cell bodies and processes of other GAD67-positive cells. These changes are associated with increased expression of acetylated tubulin, microtubule-associated protein 2 (MAP2) and the post-synaptic density protein 95 (PSD95). The addition of BDNF, together with PDGF, increases the levels of mRNA and protein for GAD67, as well as the high affinity GABA uptake protein, GAT1. These changes are associated with increased concentrations of GABA in the cytoplasm of “differentiated” HiB5 neurons. In the presence of Ca2+ and K+, newly synthesized GABA is released extracellularly. When the HiB5 cells appear to be fully differentiated, they also express GAD65, parvalbumin and calbindin, and GluR subtypes as well as HDAC1, DAXX, PAX5, Runx2, associated with GAD67 regulation. Overall, these results suggest that the HiB5 cells can differentiate into functionally mature GABA neurons in the presence of gene products that are associated with GAD67 regulation in the adult hippocampus. PMID:22457755

Subburaju, Sivan; Benes, Francine M.



Responses of substantia nigra pars reticulata neurons to benzodiazepine ligands after acute and prolonged diazepam exposure. I. Modulation of gamma-aminobutyric acid sensitivity.  


We have examined the ability of the benzodiazepine inverse agonist, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), and the antagonist, Ro15-1788, to modulate gamma-amino-butyric acid (GABA) sensitivity of reticulata neurons after chronic (3 week) and acute (1 hr) diazepam exposure. Sensitivity to GABA was analyzed by monitoring single unit responses to microiontophoretically applied GABA. The inverse agonist DMCM decreased GABA sensitivity of reticulata neurons to similar levels in control, chronic diazepam and acute diazepam-treated groups. Ro15-1788 administration reversed the effects of DMCM on GABA sensitivity and also resulted in comparable levels of GABA sensitivity in all treatment groups. Thus, the ability of the inverse agonist DMCM and the antagonist Ro15-1788 to alter GABA sensitivity of reticulata neurons was not altered by diazepam treatment. However, reticulata GABA sensitivity in the absence of additional benzodiazepine ligands was enhanced in both acute and chronic diazepam groups when compared to control values. The similarity in reticulata responses after both chronic (3 week) and acute (1 hr) diazepam treatments suggests that the enhanced sensitivity to GABA merely reflects the presence of diazepam. Thus, the ability of diazepam to potentiate reticulata GABA responses does not show time-dependent changes with prolonged benzodiazepine exposure. PMID:2537420

Wilson, M A; Gallager, D W



Contents of Neo-flavored Tea (GABA Kintaro) Containing ?-Aminobutyric Acid  

NASA Astrophysics Data System (ADS)

The contents of ?-aminobutyric acid (GABA), catechins, theaflavins, caffeine and pheophorbide-a in neo-flavored tea (GABA Kintaro tea) were analyzed. 1)The amounts of GABA were increased over 1.5mg/g by means of infrared ray irradiation with agitation treatment. 2)There was a tendency for the amount of catechins to be decreased by this treatment, whereas the amount of theaflavins tended to increase with the same treatment. The composition of these contents in this GABA Kintaro tea was almost the same as that of black tea. 3)There was a tendency for the amount of caffeine to be decreased by this treatment. 4)There was a tendency for the amount of pheophorbide-a to be increased by this treatment. 5)The result of this study showed that the amounts of GABA and theaflavins in this GABA Kintaro tea were higher than ordinary green tea but contained few catechins.It became clear that the amount of pheophorbide-a in this GABA Kintaro tea was less than the standard value established in processed chlorella.

Shiraki, Yoshiya


?-Aminobutyric acid (GABA) homeostasis regulates pollen germination and polarized growth in Picea wilsonii.  


?-Aminobutyric acid (GABA) is a four-carbon non-protein amino acid found in a wide range of organisms. Recently, GABA accumulation has been shown to play a role in the stress response and cell growth in angiosperms. However, the effect of GABA deficiency on pollen tube development remains unclear. Here, we demonstrated that specific concentrations of exogenous GABA stimulated pollen tube growth in Picea wilsonii, while an overdose suppressed pollen tube elongation. The germination percentage of pollen grains and morphological variations in pollen tubes responded in a dose-dependent manner to treatment with 3-mercaptopropionic acid (3-MP), a glutamate decarboxylase inhibitor, while the inhibitory effects could be recovered in calcium-containing medium supplemented with GABA. Using immunofluorescence labeling, we found that the actin cables were disorganized in 3-MP treated cells, followed by the transition of endo/exocytosis activating sites from the apex to the whole tube shank. In addition, variations in the deposition of cell wall components were detected upon labeling with JIM5, JIM7, and aniline blue. Our results demonstrated that calcium-dependent GABA signaling regulates pollen germination and polarized tube growth in P. wilsonii by affecting actin filament patterns, vesicle trafficking, and the configuration and distribution of cell wall components. PMID:23900837

Ling, Yu; Chen, Tong; Jing, Yanping; Fan, Lusheng; Wan, Yinglang; Lin, Jinxing



Connections between EM2-containing terminals and GABA/?-opioid receptor co-expressing neurons in the rat spinal trigeminal caudal nucleus  

PubMed Central

Endomorphin-2 (EM2) demonstrates a potent antinociceptive effect via the ?-opioid receptor (MOR). To provide morphological evidence for the pain control effect of EM2, the synaptic connections between EM2-immunoreactive (IR) axonal terminals and ?-amino butyric acid (GABA)/MOR co-expressing neurons in lamina II of the spinal trigeminal caudal nucleus (Vc) were investigated in the rat. Dense EM2-, MOR- and GABA-IR fibers and terminals were mainly observed in lamina II of the Vc. Within lamina II, GABA- and MOR-neuronal cell bodies were also encountered. The results of immunofluorescent histochemical triple-staining showed that approximately 14.2 or 18.9% of GABA-IR or MOR-IR neurons also showed MOR- or GABA-immunopositive staining in lamina II; approximately 45.2 and 36.1% of the GABA-IR and MOR-IR neurons, respectively, expressed FOS protein in their nuclei induced by injecting formalin into the left lower lip of the mouth. Most of the GABA/MOR, GABA/FOS, and MOR/FOS double-labeled neurons made close contacts with EM2-IR fibers and terminals. Immuno-electron microscopy confirmed that the EM2-IR terminals formed synapses with GABA-IR or MOR-IR dendritic processes and neuronal cell bodies in lamina II of the Vc. These results suggest that EM2 might participate in pain transmission and modulation by binding to MOR-IR and GABAergic inhibitory interneuron in lamina II of the Vc to exert inhibitory effect on the excitatory interneuron in lamina II and projection neurons in laminae I and III. PMID:25386121

Li, Meng-Ying; Wu, Zhen-Yu; Lu, Ya-Cheng; Yin, Jun-Bin; Wang, Jian; Zhang, Ting; Dong, Yu-Lin; Wang, Feng



Cloning of the. gamma. -aminobutyric acid (GABA). rho. sub 1 cDNA: A GABA receptor subunit highly expressed in the retina  

SciTech Connect

Type A {gamma}-aminobutyric acid (GABA{sub A}) receptors are a family of ligand-gated chloride channels that are the major inhibitory neurotransmitter receptors in the nervous system. Molecular cloning has revealed diversity in the subunits that compose this heterooligomeric receptor, but each previously elucidated subunit displays amino acid similarity in conserved structural elements. The authors have used these highly conserved regions to identify additional members of this family by using the polymerase chain reaction (PCR). One PCR product was used to isolate a full-length cDNA from a human retina cDNA library. The mature protein predicted from this cDNA sequence is 458 amino acids long and displays between 30 and 38% amino acid similarity to the previously identified GABA{sub A} subunits. This gene is expressed primarily in the retina but transcripts are also detected in the brain, lung, and thymus. Injection of Xenopus oocytes with RNA transcribed in vitro produces a GABA-responsive chloride conductance and expression of the cDNA in COS cells yields GABA-displaceable muscimol binding. These features are consistent with our identification of a GABA subunit, GABA {rho}{sub 1}, with prominent retinal expression that increases the diversity and tissue specificity of this ligand-gated ion-channel receptor family.

Cutting, G.R.; Lu, Luo; Kasch, L.M.; Montrose-Rafizadeh, C.; Antonarakis, S.E.; Guggino, W.B.; Kazazian, H.H. Jr. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)); O'Hara, B.F.; Donovan, D.M.; Shimada, Shoichi (National Inst. on Drug Abuse, Baltimore, MD (United States)); Uhl, G.R. (National Inst. on Drug Abuse, Baltimore, MD (United States) Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States))



GABA shunt and polyamine degradation pathway on ?-aminobutyric acid accumulation in germinating fava bean (Vicia faba L.) under hypoxia.  


GABA shunt and polyamine degradation pathway on ?-aminobutyric acid (GABA) accumulation in germinating fava bean under hypoxia was investigated. GABA content, GAD and DAO activity were significantly increased under hypoxia treatment. Glu and polyamine contents enhanced largely and thus supplied as sufficient substrates for GABA formation. In contrast, GABA content decreased, mainly in the embryo, after removing the hypoxia stress. DAO activity, Glu and polyamines contents decreased, while an increment of GAD activity was observed. This indicated that GAD activity can be not only regulated by hypoxia, but by the rapid growth of embryo after the recovery from hypoxia stress. When treated with AG, DAO activity was almost inhibited completely, and the GABA content decreased by 32.96% and 32.07% after treated for 3 and 5 days, respectively. Hence, it can be inferred that about 30% of GABA formed in germinating fava bean under hypoxia was supplied by polyamine degradation pathway. PMID:23017406

Yang, Runqiang; Guo, Qianghui; Gu, Zhenxin



A Single Amino Acid in the Second Transmembrane Domain of GABA ? Receptors Regulates Channel Conductance  

PubMed Central

GABAC receptors, expressed predominately in vertebrate retina, are thought to be formed mainly by GABA ? subunits, each of which exhibits distinct physiological and pharmacological properties. In this study, the receptors formed by perch GABA ? subunits were expressed in HEK cells, and their single channel conductances were determined using noise analysis techniques. The receptors formed by the perch ?1A subunit gate a channel with a conductance of 0.2 pS, whereas the receptors formed by GABA ?2 subunits exhibit much higher channel conductances, i.e., 3.2 pS and 3.5 pS for perch ?2A and ?2B receptors, respectively. A comparison of the amino acid sequences of the channel- forming TMII regions of the various subunits suggested that a single amino acid at position 2? was a potential site for the large differential in conductance. We found that switching the serine residue at that site in the GABA ?2 subunit to the proline residue present in the ?1 subunit reduced the channel conductance to a level similar to that of the wild type ?1 receptor. Conversely, mutating proline to serine in the amino acid sequence of the ?1 receptor significantly increased its unitary conductance. These results indicate that a single amino acid in the TMII region plays an important role in determining the single channel conductance of the GABAC receptors. PMID:17398006

Zhu, Yujie; Ripps, Harris; Qian, Haohua



The GABA-synthetic enzyme GAD65 controls circadian activation of conditioned fear pathways.  


Circadian fluctuations of fear and anxiety symptoms are observable in persons with post-traumatic stress disorder, generalized anxiety, and panic disorder; however, the underlying neurobiological mechanisms are not sufficiently understood. In the present study, we investigated the putative role of inhibitory neurotransmission in the circadian fluctuation of fear symptoms, using mice with genetic ablation of the ?-amino butyric acid (GABA) synthesizing isoenzyme, glutamic acid decarboxylase GAD65. We observed in these mutant mice an altered expression of conditioned fear with a profound reduction of freezing, and an increase of hyperactivity bouts occurring only when both fear conditioning training and retrieval testing were done at the beginning of their active phase. Mutants further showed an increased arousal response at this time of the day, although, circadian rhythm of home cage activity was unaltered. Hyperactivity and reduced freezing during fear memory retrieval were accompanied by an increased induction of the immediate early gene cFos suggesting hyperactivation of the hippocampus, amygdala, and medial hypothalamus. Our data suggest a role of GAD65-mediated GABA synthesis in the encoding of circadian information to fear memory. GAD65 deficits in a state-dependent manner result in increased neural activation in fear circuits and elicit panic-like flight responses during fear memory retrieval. PMID:24300892

Bergado-Acosta, Jorge R; Müller, Iris; Richter-Levin, Gal; Stork, Oliver



Does pipecolic acid interact with the central GABA-ergic system?  

Microsoft Academic Search

Summary Several previous studies have suggested a strong GABA-mimetic action of the endogenous brain imino acid, L-pipecolic acid (L-PA). In the present study, these observations were evaluated using electrophysiological and neurochemical methods. In contrast to published data our electrophysiological studies on rat cortical neuronesin situ showed only a weak, but bicuculline-sensitive depressant action of L-PA on cortical neurones.

R. Bernasconi; R. S. G. Jones; H. Bittiger; H. R. Olpe; J. Heid; P. Martin; M. Klein; P. Loo; A. Braunwalder; M. Schmutz



Oxidative stress mediated neuronal damage in the corpus striatum of 6-hydroxydopamine lesioned Parkinson's rats: neuroprotection by serotonin, GABA and bone marrow cells supplementation.  


Oxidative stress-induced neuronal cell death has been implicated in Parkinson's disease (PD). Oxidative stress initiated by 6-hydroxydopamine (6-OHDA) causes mitochondrial dysfunction leading to apoptosis and Parkinsonian neurodegeneration. We investigated the neuroprotective potential of serotonin (5-HT), gamma amino butyric acid (GABA) and autologous bone marrow cells (BMC) in combination against oxidative stress-induced cell death. PD was induced in adult male Wistar rats by intranigral infusion of 6-OHDA (8 ?g/?l). The activities of antioxidant enzymes--superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were analysed. The extent of lipid peroxidation was quantified by measuring the formation of thiobarbituric acid reactive substances (TBARs). Real Time PCR gene expression of SOD, CAT and GPx were performed using specific Taqman probes. 6-OHDA induced decreased activity of SOD, CAT and GPx in corpus striatum was significantly reversed to near control (p<0.001) by treatment with 5-HT, GABA and bone marrow cells. Gene expression studies of SOD, CAT and GPx using Real Time PCR confirmed the above observation. TBAR levels were elevated (p<0.001) in 6-OHDA treated rats indicating lipid peroxidation. 5-HT and GABA along with autologous bone marrow cell supplementation significantly ameliorated 6-OHDA-induced lipid peroxidation (p<0.001). Our results suggest a new therapeutic strategy of neuroprotection against damage by oxidative stress in Parkinson's disease. PMID:23726276

Kuruvilla, Korah P; Nandhu, M S; Paul, Jes; Paulose, C S



Glutamate and GABA contributions to medial prefrontal cortical activity to emotion: implications for mood disorders.  


The dorsomedial prefrontal cortex (MdPFC) and anterior cingulate cortices (ACC) play a critical role in implicit emotion regulation; however the understanding of the specific neurotransmitters that mediate such role is lacking. In this study, we examined relationships between MdPFC concentrations of two neurotransmitters, glutamate and ?-amino butyric acid (GABA), and BOLD activity in ACC during performance of an implicit facial emotion-processing task. Twenty healthy volunteers, aged 20-35 years, were scanned while performing an implicit facial emotion-processing task, whereby presented facial expressions changed from neutral to one of the four emotions: happy, anger, fear, or sad. Glutamate concentrations were measured before and after the emotion-processing task in right MdPFC using magnetic resonance spectroscopy (MRS). GABA concentrations were measured in bilateral MdPFC after the emotion-processing task. Multiple regression models were run to determine the relative contribution of glutamate and GABA concentration, age, and gender to BOLD signal in ACC to each of the four emotions. Multiple regression analyses revealed a significant negative correlation between MdPFC GABA concentration and BOLD signal in subgenual ACC (p<0.05, corrected) to sad versus shape contrast. For the anger versus shape contrast, there was a significant negative correlation between age and BOLD signal in pregenual ACC (p<0.05, corrected) and a positive correlation between MdPFC glutamate concentration (pre-task) and BOLD signal in pregenual ACC (p<0.05, corrected). Our findings are the first to provide insight into relationships between MdPFC neurotransmitter concentrations and ACC BOLD signal, and could further understanding of molecular mechanisms underlying emotion processing in healthy and mood-disordered individuals. PMID:24973815

Stan, Ana D; Schirda, Claudiu V; Bertocci, Michele A; Bebko, Genna M; Kronhaus, Dina M; Aslam, Haris A; LaBarbara, Eduard J; Tanase, Costin; Lockovich, Jeanette C; Pollock, Myrna H; Stiffler, Richelle S; Phillips, Mary L



Acute effects of sodium valproate and ?-vinyl gaba on regional amino acid metabolism in the rat brain: Incorporation of 2-[ 14 C]glucose into amino acids  

Microsoft Academic Search

Amino acid concentrations have been determined in rat brain regions (cortex, striatum, cerebellum, and hippocampus) by HPLC after administration of acute anticonvulsant doses of sodium valproate (400 mg\\/kg, i.p.) and ?-vinyl-GABA (1g\\/kg, i.p.). After valproate administration the GABA level increases only in the cortex; aspartic acid concentration decreases in the cortex and hippocampus, and glutamic acid decreases in the hippocampus

A. G. Chapman; K. Riley; M. C. Evans; B. S. Meldrum



Disturbance of neural respiratory control in neonatal mice lacking gaba synthesizing enzyme 67-kda isoform of glutamic acid decarboxylase  

Microsoft Academic Search

To examine the role of GABA in the respiratory rhythm and pattern generation in neonatal mice, we analyzed the function of the respiratory control system of 67-kDa isoform of glutamic acid decarboxylase (GAD67)-deficient neonatal mice. In these mutant (GAD67?\\/?) mice, GABA levels in the brainstem were reduced to about 30% of those in wild-type (GAD67+\\/+) mice. In in vivo preparations,

S Kuwana; Y Okada; Y Sugawara; N Tsunekawa; K Obata



Glutamic Acid Decarboxylase Activity of Mycobacterium leprae and Occurrence of gamma-Amino Butyric Acid in Skin Lesions of Leprosy  

Microsoft Academic Search

IN 1872 Hansen characterized Mycobacterium leprae as the causative agent in human leprosy. Hitherto, all attempts to cultivate this organism in vitro or to transmit it to experimental animals have met with little success, and the metabolism of this micro-organism has remained completely unknown.

K. Prabhakaran; Beatriz M. Braganca



Molecular and Therapeutic Potential and Toxicity of Valproic Acid  

PubMed Central

Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels. VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. VPA is a widely used drug, particularly for children suffering from epilepsy. Due to the increasing number of clinical trials involving VPA, and interesting results obtained, this molecule will be implicated in an increasing number of therapies. However side effects of VPA are substantially described in the literature whereas they are poorly discussed in articles focusing on its therapeutic use. This paper aims to give an overview of the different clinical-trials involving VPA and its side effects encountered during treatment as well as its molecular properties. PMID:20798865

Chateauvieux, Sebastien; Morceau, Franck; Dicato, Mario; Diederich, Marc



Manganese accumulation in membrane fractions of primary astrocytes is associated with decreased ?-aminobutyric acid (GABA) uptake, and is exacerbated by oleic acid and palmitate.  


Manganese (Mn) exposure interferes with GABA uptake; however, the effects of Mn on GABA transport proteins (GATs) have not been identified. We sought to characterize how Mn impairs GAT function in primary rat astrocytes. Astrocytes exposed to Mn (500 ?M) had significantly reduced (3)H-GABA uptake despite no change in membrane or cytosolic GAT3 protein levels. Co-treatment with 100 ?M oleic or palmitic acids (both known to be elevated in Mn neurotoxicity), exacerbated the Mn-induced decline in (3)H-GABA uptake. Mn accumulation in the membrane fraction of astrocytes was enhanced with fatty acid administration, and was negatively correlated with (3)H-GABA uptake. Furthermore, control cells exposed to Mn only during the experimental uptake had significantly reduced (3)H-GABA uptake, and the addition of GABA (50 ?M) blunted cytosolic Mn accumulation. These data indicate that reduced GAT function in astrocytes is influenced by Mn and fatty acids accumulating at or interacting with the plasma membrane. PMID:24814258

Fordahl, Steve C; Erikson, Keith M



Effects of the gamma-aminobutyrate transaminase inhibitors gabaculine and gamma-vinyl GABA on gamma-aminobutyric acid release from slices of rat cerebral cortex  

SciTech Connect

The release of (/sup 3/H)gamma-aminobutyric acid (GABA) from pre-loaded slices of rat cerebral cortex was investigated in the presence and absence of the GABA-transaminase inhibitors gabaculine and gamma-vinyl GABA. In the experiments carried out without an inhibitor, an ion-exchange column chromatographic technique was used to separate (/sup 3/H)GABA from tritiated metabolites released with it into the superfusate. The presence of gabaculine (5 microM) substantially reduced the Ca2+-dependence of the release of (/sup 3/H)GABA evoked by a 4 min 30 mM K+ pulse, whereas this was not appreciably reduced by the presence of gamma-vinyl GABA (2 mM or 10 mM). Nevertheless, the characteristics of (/sup 3/H)GABA release were not identical in the presence and absence of either inhibitor.

Bedwani, J.R.; Mehta, A.



Exogenous ?-aminobutyric acid (GABA) affects pollen tube growth via modulating putative Ca2+-permeable membrane channels and is coupled to negative regulation on glutamate decarboxylase.  


?-Aminobutyric acid (GABA) is implicated in pollen tube growth, but the molecular and cellular mechanisms that it mediates are largely unknown. Here, it is shown that exogenous GABA modulates putative Ca(2+)-permeable channels on the plasma membranes of tobacco pollen grains and pollen tubes. Whole-cell voltage-clamp experiments and non-invasive micromeasurement technology (NMT) revealed that the influx of Ca(2+) increases in pollen tubes in response to exogenous GABA. It is also demonstrated that glutamate decarboxylase (GAD), the rate-limiting enzyme of GABA biosynthesis, is involved in feedback controls of Ca(2+)-permeable channels to fluctuate intracellular GABA levels and thus modulate pollen tube growth. The findings suggest that GAD activity linked with Ca(2+)-permeable channels relays an extracellular GABA signal and integrates multiple signal pathways to modulate tobacco pollen tube growth. Thus, the data explain how GABA mediates the communication between the style and the growing pollen tubes. PMID:24799560

Yu, Guang-Hui; Zou, Jie; Feng, Jing; Peng, Xiong-Bo; Wu, Ju-You; Wu, Ying-Liang; Palanivelu, Ravishankar; Sun, Meng-Xiang




EPA Science Inventory

The ventral hippocampi of male, Fischer-344 rats were implanted with microdialysis probes and the effects of systemically administered kainic acid (KA) (8 mg/kg, s.c.) on the in vivo release of amino acids were measured for four hours after administration. n order to measure GABA...


Modulation of gamma-aminobutyric acid (GABA) receptors and the feeding response by neurosteroids in Hydra vulgaris.  


Gamma-Aminobutyric acid (GABA) receptors are present in membrane preparations from Hydra vulgaris, one of the most primitive organisms with a nervous system. These receptors are sensitive to muscimol and benzodiazepines and appear to be important in the regulation of the feeding response. The effects of neurosteroids, general anaesthetics, and GABA antagonists on GABA(A) receptors in membranes prepared from Hydra and on the feeding response have now been investigated. The neurosteroids tetrahydroprogesterone and tetrahydrodeoxycorticosterone increased [3H]GABA binding to hydra membranes with nanomolar potency (EC50, 141+/-11 and 623+/-36 nM, respectively) and high efficacy (maximal increase 79+/-6.5 and 62+/-4%, respectively), whereas the 3beta-hydroxy epimer of tetrahydroprogesterone was ineffective. The benzodiazepine receptor ligands diazepam (100 microM), clonazepam (100 microM) and abecarnil (30 microM) enhanced [3H]GABA binding to Hydra membranes by 22, 20 and 24%, respectively; effects abolished by the specific benzodiazepine antagonist flumazenil (100 microM). On the contrary, the peripheral benzodiazepine receptor ligand 4'chlorodiazepam failed to affect [3H]GABA binding to Hydra membranes. The general anaesthetics propofol and alphaxalone similarly increased (+38% and +30% respectively) [3H]GABA binding. Moreover, [3H]GABA binding to Hydra membranes was completely inhibited by the GABA(A) receptor antagonist SR 95531, whereas bicuculline was without effect. The modulation of GABA(A) receptors in vitro by these various drugs correlated with their effects on the glutathione-induced feeding response in the living animals. Tetrahydroprogesterone and tetrahydrodeoxy-corticosterone (1 to 10 microM) prolonged, in a dose-dependent manner, the duration of mouth opening induced by 10 microM glutathione, with maximal effects of +33 and +29%, respectively, apparent at 10 microM neurosteroid. Alphaxalone (10 microM) similarly increased (+33%) the effect of glutathione. The effects of steroids on the feeding response were inhibited by SR 95531 in a dose-dependent manner; t-butylbyclophosphorothyonate (1 microM), a specific Cl- channel blocker, which per se, like picrotoxin but not bicuculline, shortened the duration of the response, also counteracted the steroids effects at 1 microM. These results suggest that the modulation of GABA(A) receptors by steroids is an ancient characteristic of the animal kingdom and that the pharmacological properties of these receptors have been highly conserved through evolution. PMID:9639289

Concas, A; Pierobon, P; Mostallino, M C; Porcu, P; Marino, G; Minei, R; Biggio, G



The dual effects of GABA and related amino acids on the electrical threshold of ventral horn group Ia afferent terminations in the cat  

Microsoft Academic Search

Amino acids were administered microelectrophoretically near the unmyelinated terminations of extensor muscle Ia afferent terminations stimulated electrically in the vicinity of lumbar motoneurones in anaesthetized cats. The predominant effect of one group (structurally related to GABA, poor substrates for in vitro amino acid uptake systems) was a reduction in the threshold (depolarization). The second group (including GABA and structural analogues

D. R. Curtis; D. Lodge; J. C. Bornstein; M. J. Peet; J. D. Lean



Lesions of nucleus accumbens affect morphine-induced release of ascorbic acid and GABA but not of glutamate in rats.  


Our previous studies have shown that local perfusion of morphine causes an increase of extracellular ascorbic acid (AA) levels in nucleus accumbens (NAc) of freely moving rats. Lines of evidence showed that glutamatergic and GABAergic were associated with morphine-induced effects on the neurotransmission of the brain, especially on the release of AA. In the present study, the effects of morphine on the release of extracellular AA, ?-aminobutyric acid (GABA) and glutamate (Glu) in the NAc following bilateral NAc lesions induced by kainic acid (KA) were studied by using the microdialysis technique, coupled to high performance liquid chromatography with electrochemical detection (HPLC-ECD) and fluorescent detection (HPLC-FD). The results showed that local perfusion of morphine (100 µM, 1 mM) in NAc dose-dependently increased AA and GABA release, while attenuated Glu release in the NAc. Naloxone (0.4 mM) pretreated by local perfusion to the NAc, significantly blocked the effects of morphine. After NAc lesion by KA (1 µg), morphine-induced increase in AA and GABA were markedly eliminated, while decrease in Glu was not affected. The loss effect of morphine on AA and GABA release after KA lesion could be recovered by GABA agonist, musimol. These results indicate that morphine-induced AA release may be mediated at least by µ-opioid receptor. Moreover, this effect of morphine possibly depend less on the glutamatergic afferents, but more on the GABAergic circuits within this nucleus. Finally, AA release induced by local perfusion of morphine may be GABA-receptor mediated and synaptically localized in the NAc. PMID:20731632

Sun, Ji Y; Yang, Jing Y; Wang, Fang; Wang, Jian Y; Song, Wu; Su, Guang Y; Dong, Ying X; Wu, Chun F



Variation of glutamate decarboxylase activity and gamma-amino butyric acid content of wheat embryos during ripening of seeds.  


GAD activity and gamma-ABA content of wheat embryos at 7 ripening stages were verified with the aim of studying the metabolic activity of embryo during dehydration and quiescence of caryopsis. Data showed that in the early stage of ripening GAD activity is very low, increases rapidly at dough-stage, remaining constant up to waxy-stage, and decreases in the last fully-ripe embryos. gamma-ABA content appears to be roughly parallel to the variations of GAD activity. PMID:590443

Galleschi, L; Floris, C; Cozzani, I



Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase  

Microsoft Academic Search

The pancreatic islet beta-cell autoantigen of relative molecular mass 64,000 (64K), which is a major target of autoantibodies associated with the development of insulin-dependent diabetes mel-litus (IDDM) has been identified as glutamic acid decarboxylase, the biosynthesizing enzyme of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). Pancreatic beta cells and a subpopulation of central nervous system neurons express high levels of this

Steinunn Baekkeskov; Henk-Jan Aanstoot; Stephan Christgai; Annette Reetz; Michele Solimena; Marilia Cascalho; Franco Folli; Hanne Richter-Olesen; Pietro-De Camilli



Inhibition of GABA-gated chloride channels by 12,14-dichlorodehydroabietic acid in mammalian brain  

PubMed Central

12,14-dichlorodehydroabietic acid (12,14-Cl2DHA) reduced GABA-stimulated uptake of 36Cl? into mouse brain synaptoneurosomes suggesting inhibition of mammalian GABAA receptor function. 12,14-Cl2DHA did not affect the binding of [3H]-muscimol to brain membranes but displaced specifically bound [3H]-EBOB. The inhibitory effect on [3H]-EBOB binding was not reversible. 12,14-Cl2DHA reduced the availability of [3H]-EBOB binding sites (Bmax) without changing the KD of the radioligand for remaining sites. 12,14-Cl2DHA did not affect the rate of association of [3H]-EBOB with its chloride channel receptor, but increased the initial rate of [3H]-EBOB dissociation. 12,14-Cl2DHA enhanced the incidence of EPSCs when rapidly applied to cultured rat cortical neurones. Longer exposures produced block of IPSCs with marked increases in the frequency of EPSCs and min EPSCs. 12,14-Cl2DHA also irreversibly suppressed chloride currents evoked by pulses of exogenous GABA in these cells. Ultimately, 12,14-Cl2DHA inhibited all synaptic traffic and action currents in current clamped cells indicating that, in contrast to picrotoxinin (which causes paroxysmal bursting), it is not fully selective for the GABAA receptor-chloride channel complex. The depolarizing block seen with 12,14-Cl2DHA in amphotericin-perforated preparations implicates loss of Ca2+ buffering in the polarity change and this may account for inhibition of spontaneous action potentials. Our investigation demonstrates that 12,14-Cl2DHA blocks GABA-dependent chloride entry in mammalian brain and operates as a non-competitive insurmountable GABAA antagonist. The mechanism likely involves either irreversible binding of 12,14-Cl2DHA to the trioxabicyclooctane recognition site or a site that is allosterically coupled to it. We cannot exclude, however, the possibility that 12,14-Cl2DHA causes localized proteolysis or more extensive conformational change within a critical subunit of the chloride channel. PMID:10204999

Nicholson, Russell A; Lees, George; Zheng, Jian; Verdon, Bernard



31923202 Nucleic Acids Research, 2007, Vol. 35, No. 10 Published online 22 April 2007 doi:10.1093/nar/gkm187  

E-print Network

of Genetics and Center for Genome Sciences, Washington University in St Louis, 4444 Forest Park Parkway--both the g-amino-butyric acid type A receptor gamma-subunit (GABAAR g2) gene and the myosin light chain

Mitra, Rob


GABA A receptors as in vivo substrate for the anxiolytic action of valerenic acid, a major constituent of valerian root extracts.  


Valerian extracts have been used for centuries to alleviate restlessness and anxiety albeit with unknown mechanism of action in vivo. We now describe a specific binding site on GABA(A) receptors with nM affinity for valerenic acid and valerenol, common constituents of valerian. Both agents enhanced the response to GABA at multiple types of recombinant GABA(A) receptors. A point mutation in the beta2 or beta3 subunit (N265M) of recombinant receptors strongly reduced the drug response. In vivo, valerenic acid and valerenol exerted anxiolytic activity with high potencies in the elevated plus maze and the light/dark choice test in wild type mice. In beta3 (N265M) point-mutated mice the anxiolytic activity of valerenic acid was absent. Thus, neurons expressing beta3 containing GABA(A) receptors are a major cellular substrate for the anxiolytic action of valerian extracts. PMID:18602406

Benke, Dietmar; Barberis, Andrea; Kopp, Sascha; Altmann, Karl-Heinz; Schubiger, Monika; Vogt, Kaspar E; Rudolph, Uwe; Möhler, Hanns



2005 Nature Publishing Group GABA (-aminobutyric acid) is the main inhibitory  

E-print Network

) receptors, is to increase membrane permeability to chloride and bi- carbonate ions.In most mature R E V I E W S of GABA transporters and postsynaptic receptors in relation to the

Sandini, Giulio


Detection of amino acid neurotransmitters by surface enhanced Raman scattering and hollow core photonic crystal fiber  

NASA Astrophysics Data System (ADS)

The present work explores the feasibility of using surface enhanced Raman scattering (SERS) for detecting the neurotransmitters such as glutamate (GLU) and gamma-amino butyric acid (GABA). These amino acid neurotransmitters that respectively mediate fast excitatory and inhibitory neurotransmission in the brain, are important for neuroendocrine control, and upsets in their synthesis are also linked to epilepsy. Our SERS-based detection scheme enabled the detection of low amounts of GLU (10-7 M) and GABA (10-4 M). It may complement existing techniques for characterizing such kinds of neurotransmitters that include high-performance liquid chromatography (HPLC) or mass spectrography (MS). This is mainly because SERS has other advantages such as ease of sample preparation, molecular specificity and sensitivity, thus making it potentially applicable to characterization of experimental brain extracts or clinical diagnostic samples of cerebrospinal fluid and saliva. Using hollow core photonic crystal fiber (HC-PCF) further enhanced the Raman signal relative to that in a standard cuvette providing sensitive detection of GLU and GABA in micro-litre volume of aqueous solutions.

Tiwari, Vidhu S.; Khetani, Altaf; Monfared, Ali Momenpour T.; Smith, Brett; Anis, Hanan; Trudeau, Vance L.



Presumed case of "stiff-horse syndrome" caused by decreased gamma-aminobutyric acid (GABA) production in an American Paint mare  

PubMed Central

Glutamic acid decarboxylase (GAD) converts glutamic acid into the inhibitory neurotransmitter ?-aminobutyric acid (GABA). Increased serum GAD (auto) antibody concentrations were found in a mare with increased postural musculature tone resulting in stiffness and recumbence. The mare was treated with dexamethasone which resulted in resolution of clinical signs and decreased GAD antibody concentrations. PMID:22753968

Purcell, Tawna Backman; Sellers, Ann Davidson; Goehring, Lutz S.



Probing Structural Features and Binding Mode of 3-Arylpyrimidin-2,4-diones within Housefly ?-Aminobutyric Acid (GABA) Receptor  

PubMed Central

In order to obtain structural features of 3-arylpyrimidin-2,4-diones emerged as promising inhibitors of insect ?-aminobutyric acid (GABA) receptor, a set of ligand-/receptor-based 3D-QSAR models for 60 derivatives are generated using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA). The statistically optimal CoMSIA model is produced with highest q2 of 0.62, r2ncv of 0.97, and r2pred of 0.95. A minor/bulky electronegative hydrophilic polar substituent at the 1-/6-postion of the uracil ring, and bulky substituents at the 3?-, 4?- and 5?-positions of the benzene ring are beneficial for the enhanced potency of the inhibitors as revealed by the obtained 3D-contour maps. Furthermore, homology modeling, molecular dynamics (MD) simulation and molecular docking are also carried out to gain a better understanding of the probable binding modes of these inhibitors, and the results show that residues Ala-183(C), Thr-187(B), Thr-187(D) and Thr-187(E) in the second transmembrane domains of GABA receptor are responsible for the H-bonding interactions with the inhibitor. The good correlation between docking observations and 3D-QSAR analyses further proves the model reasonability in probing the structural features and the binding mode of 3-arylpyrimidin-2,4-dione derivatives within the housefly GABA receptor. PMID:22016659

Li, Qinfan; Zhang, Lihui; Ma, Zhi; Kong, Xiangya; Wang, Fangfang; Zhang, Hong; Wang, Yonghua



Epoxy Fatty Acids and Inhibition of the Soluble Epoxide Hydrolase Selectively Modulate GABA Mediated Neurotransmission to Delay Onset of Seizures  

PubMed Central

In the brain, seizures lead to release of large amounts of polyunsaturated fatty acids including arachidonic acid (ARA). ARA is a substrate for three major enzymatic routes of metabolism by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes. These enzymes convert ARA to potent lipid mediators including prostanoids, leukotrienes and epoxyeicosatrienoic acids (EETs). The prostanoids and leukotrienes are largely pro-inflammatory molecules that sensitize neurons whereas EETs are anti-inflammatory and reduce the excitability of neurons. Recent evidence suggests a GABA-related mode of action potentially mediated by neurosteroids. Here we tested this hypothesis using models of chemically induced seizures. The level of EETs in the brain was modulated by inhibiting the soluble epoxide hydrolase (sEH), the major enzyme that metabolizes EETs to inactive molecules, by genetic deletion of sEH and by direct administration of EETs into the brain. All three approaches delayed onset of seizures instigated by GABA antagonists but not seizures through other mechanisms. Inhibition of neurosteroid synthesis by finasteride partially blocked the anticonvulsant effects of sEH inhibitors while the efficacy of an inactive dose of neurosteroid allopregnanolone was enhanced by sEH inhibition. Consistent with earlier findings, levels of prostanoids in the brain were elevated. In contrast, levels of bioactive EpFAs were decreased following seizures. Overall these results demonstrate that EETs are natural molecules which suppress the tonic component of seizure related excitability through modulating the GABA activity and that exploration of the EET mediated signaling in the brain could yield alternative approaches to treat convulsive disorders. PMID:24349022

Inceoglu, Bora; Zolkowska, Dorota; Yoo, Hyun Ju; Wagner, Karen M.; Yang, Jun; Hackett, Edward; Hwang, Sung Hee; Lee, Kin Sing Stephen; Rogawski, Michael A.; Morisseau, Christophe; Hammock, Bruce D.



Gaba and hepatocellular carcinoma  

Microsoft Academic Search

Data derived from models of hepatic regeneration indicate that transient, recipricol changes in polyamines, potent growth promoters, and gamma aminobutyric acid (GABA), an amino acid neurotransmitter with growth inhibitory properties, play important roles in enhancing and inhibiting respectively regulated hepatocyte proliferation. Based on these findings and supportive data derived from studies of human carcinoma tissues and malignant cell lines we

G. Y. Minuk



Retinoic Acid, GABA-ergic, and TGF-? Signaling Systems Are Involved in Human Cleft Palate Fibroblast Phenotype  

PubMed Central

During embryogenesis, a complex interplay between extracellular matrix (ECM) molecules, regulatory molecules, and growth factors mediates morphogenetic processes involved in palatogenesis. Transforming growth factor-? (TGF-?), retinoic acid (RA), and ?-aminobutyric acid (GABA)ergic signaling systems are also potentially involved. Using [3H]glucosamine and [35S]methionine incorporation, anion exchange chromatography, semiquantitative radioactive RT-PCR, and a TGF-? binding assay, we aimed to verify the presence of phenotypic differences between primary cultures of secondary palate (SP) fibroblasts from 2-year-old subjects with familial nonsyndromic cleft lip and/or palate (CLP-SP fibroblasts) and age-matched normal SP (N-SP) fibroblasts. The effects of RA—which, at pharmacologic doses, induces cleft palate in newborns of many species—were also studied. We found an altered ECM production in CLP-SP fibroblasts that synthesized and secreted more glycosaminoglycans (GAGs) and fibronectin (FN) compared with N-SP cells. In CLP-SP cells, TGF-?3 mRNA expression and TGF-? receptor number were higher and RA receptor-? (RARA) gene expression was increased. Moreover, we demonstrated for the first time that GABA receptor (GABRB3) mRNA expression was upregulated in human CLP-SP fibroblasts. In N-SP and CLP-SP fibroblasts, RA decreased GAG and FN secretion and increased TGF-?3 mRNA expression but reduced the number of TGF-? receptors. TGF-? receptor type I mRNA expression was decreased, TGF-? receptor type II was increased, and TGF-? receptor type III was not affected. RA treatment increased RARA gene expression in both cell populations but upregulated GABRB3 mRNA expression only in N-SP cells. These results show that CLP-SP fibroblasts compared with N-SP fibroblasts exhibit an abnormal phenotype in vitro and respond differently to RA treatment, and suggest that altered crosstalk between RA, GABAergic, and TGF-? signaling systems could be involved in human cleft palate fibroblast phenotype. PMID:17225872

Baroni, Tiziano; Bellucci, Catia; Lilli, Cinzia; Pezzetti, Furio; Carinci, Francesco; Becchetti, Ennio; Carinci, Paolo; Stabellini, Giordano; Calvitti, Mario; Lumare, Eleonora; Bodo, Maria



Disinhibitory behavior and GABA A receptor function in serotonin-depleted adult male rats are reduced by gonadectomy  

Microsoft Academic Search

Impulsive and aggressive behaviors in, e.g., personality or substance abuse disorders in man and corresponding behaviors in rats may involve serotonin (5-HT), ?-amino-butyric acidA\\/benzodiazepine receptor complexes (GABAA\\/BDZ-RC) and steroid hormones, e.g., testosterone. Here, we studied the effect of gonadectomy on disinhibitory behavior in individually housed 5-HT-depleted rats and on GABAA\\/BDZ-RC function in vitro, in corticohippocampal synaptoneurosomes prepared from the brain

Anders I Svensson; Anders Berntsson; Jörgen A Engel; Bo Söderpalm



Amino acid signatures in the developing mouse retina.  


This study characterizes the developmental patterns of seven key amino acids: glutamate, ?-amino-butyric acid (GABA), glycine, glutamine, aspartate, alanine and taurine in the mouse retina. We analyze amino acids in specific bipolar, amacrine and ganglion cell sub-populations (i.e. GABAergic vs. glycinergic amacrine cells) and anatomically distinct regions of photoreceptors and Müller cells (i.e. cell bodies vs. endfeet) by extracting data from previously described pattern recognition analysis. Pattern recognition statistically classifies all cells in the retina based on their neurochemical profile and surpasses the previous limitations of anatomical and morphological identification of cells in the immature retina. We found that the GABA and glycine cellular content reached adult-like levels in most neurons before glutamate. The metabolic amino acids glutamine, aspartate and alanine also reached maturity in most retinal cells before eye opening. When the overall amino acid profiles were considered for each cell group, ganglion cells and GABAergic amacrine cells matured first, followed by glycinergic amacrine cells and finally bipolar cells. Photoreceptor cell bodies reached adult-like amino acid profiles at P7 whilst Müller cells acquired typical amino acid profiles in their cell bodies at P7 and in their endfeet by P14. We further compared the amino acid profiles of the C57Bl/6J mouse with the transgenic X-inactivation mouse carrying the lacZ gene on the X chromosome and validated this animal model for the study of normal retinal development. This study provides valuable insight into normal retinal neurochemical maturation and metabolism and benchmark amino acid values for comparison with retinal disease, particularly those which occur during development. PMID:24368173

Nivison-Smith, Lisa; Chua, Jacqueline; Tan, Seong-Seng; Kalloniatis, Michael



Phosphinic acid analogues of GABA are antagonists at the GABAB receptor in the rat anococcygeus.  

PubMed Central

CGP 35348 (3-aminopropyl(diethoxymethyl)phosphinic acid) and 3-aminopropyl(n-hexyl)phosphinic acid (3-APHPA) were tested in the rat anococcygeus muscle against CGP 27492 (3-aminopropylphosphinic acid), a selective GABAB agonist, for their antagonist activity. Their antagonist potency was compared with that of 2-hydroxysaclofen. The pA2 values for CGP 35348, 3-APHPA and 2-hydroxysaclofen were 5.38, 4.86, 4.45 respectively in the rat anococcygeus muscle. These results confirm the previous reports of GABAB antagonist activity for these compounds and show a marginal improvement in potency over 2-hydroxysaclofen. PMID:1646062

Hills, J. M.; Sellers, A. J.; Mistry, J.; Broekman, M.; Howson, W.



Glutamate and GABA-metabolizing enzymes in post-mortem cerebellum in Alzheimer's disease: phosphate-activated glutaminase and glutamic acid decarboxylase.  


Enzymes of glutamate and GABA metabolism in postmortem cerebellum from patients with Alzheimer's disease (AD) have not been comprehensively studied. The present work reports results of original comparative study on levels of phosphate-activated glutaminase (PAG) and glutamic acid decarboxylase isoenzymes (GAD65/67) in autopsied cerebellum samples from AD patients and matched controls (13 cases in each group) as well as summarizes published evidence for altered levels of PAG and GAD65/67 in AD brain. Altered (decreased) levels of these enzymes and changes in links between amounts of these enzymes and other glutamate-metabolizing enzymes (such as glutamate dehydrogenase and glutamine synthetase-like protein) in AD cerebella suggest significantly impaired glutamate and GABA metabolism in this brain region, which was previously regarded as not substantially involved in AD pathogenesis. PMID:24950944

Burbaeva, G Sh; Boksha, I S; Tereshkina, E B; Savushkina, O K; Prokhorova, T A; Vorobyeva, E A



GABA Neurotransmitter  

NSDL National Science Digital Library

GABA occurs in 30-40% of all synapses-only glutamate is more widely distributed. Neurons in every region of the brain use GABA to fine-tune neurotransmission. Increasing GABA at the neuronal synapse inhibits the generation of the action potential of the neuron, thereby making it less likely to excite nearby neurons. A single neuron may have thousands of other neurons synapsing onto it. Some of these release activating (or depolarizing) neurotransmitters; others release inhibitory (or hyperpolarizing) neurotransmitters. GABA is the primary inhibitory neurotransmitter, which means it decreases the neuron's action potential. When the action potential drops below a certain level, known as the threshold potential, the neuron will not generate action potentials and thus not excite nearby neurons. The nucleus of a neuron is located in the cell body. Extending out from the cell body are dendrites and axons. Dendrites conduct impulses toward the cell body, Axons conducting impulses away from the cell body. A recording electrode has been attached to a voltmeter to record the charge across the cell membrane, the thin layer that controls movement in and out of the neuron. The resting potential in excitable neurons is usually around -65 to -70 millivolts (mV), which can be seen on the voltmeter. Excitatory synapses reduce the membrane potential: The synapses labeled A, B, and C are excitatory (e.g. glutamate ACH). These synapses release activating neurotransmitters, which reduce the resting potential of the neuron. If the voltage reaches the threshold potential, typically around -50 mv, an action potential is generated, which will travel down the axon, where it will communicate with a nearby cell. The strength of the stimuli that produce an action potential is important only insomuch as it reaches threshold potential. The resultant action potential is always the same, whether it was created by relatively strong or relatively weak stimuli. action potential is a constant. Decreasing the action potential: GABA is the primary inhibitory neurotransmitter, which means it decreases the neuronâÃÂÃÂs action potential. When the action potential drops below the threshold potential, the neuron will not excite nearby neurons. Exitatory PostSynaptic Potential (EPSP): The Exitatory PostSynaptic Potential (EPSP) of a single excitatory synapse is not sufficient to reach the threshold of the neuron. Rather, when a number of EPSPs are created in quick succession, their charges sum together. It is the combined sum of these EPSPs that creates an action potential Activation of inhibitory synapses such as GABA, on the other hand, makes resting potential more negative. This hyperpolarization is called an inhibitory postsynaptic potential (IPSP). Activation of inhibitory synapses (D and E) makes the resting potential of the neuron more negative. The resulting IPSP may also prevent what would otherwise have been effective EPSPs from triggering an action potential. It is the total summation of the EPSPs and IPSPs that determines whether a neuronâÃÂÃÂs charge is sufficient to cross the potential threshold.



GABA B Receptors in Reward Processes  

Microsoft Academic Search

?-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the brain which acts through different receptor subtypes. Metabotropic GABAB receptors are widely distributed throughout the brain. Alterations in GABA signaling through pharmacological activation or deactivation of the GABAB receptor regulate behavior and brain reward processes. GABAB receptor agonists and, most recently, positive modulators have been found to inhibit the reinforcing

Styliani Vlachou; Athina Markou



Gamma-aminobutyric acid (GABA) and neuropeptides in neural areas mediating motion-induced emesis  

NASA Technical Reports Server (NTRS)

Immunocytochemical methods were employed to localize the neurotransmitter amino acid gamma-aminobutyric acid and the neuropeptides substance P and Met-enkephalin in the area postrema (AP), area subpostrema (ASP), nucleus of the tractus solitarius (NTS), dorsal motor nucleus of the vagus nerve (DMNV), and lateral vestibular nucleus (LVN). Glutamic acid decarboxylase immunoreactive (GAD-IR) terminals and fibers were observed in the AP and particularly in the ASP. A gradual decrease in the density of terminals was seen towards the solitary complex. The DMNV revealed irregularly scattered GAD-IR terminals within the neuropil or closely surrounding neuronal cell bodies. The LVN, particularly the dorsal division, showed numerous axon terminals which were mostly localize around large neurons and their proximal dendrites. Substance P immunoreactive (SP-IR) terminals and fibers showed high density in the solitary complex, in particular within the lateral division. The ASP showed medium to low density of SP-IR fibers and terminals. The AP exhibited a small number of fibers and terminals irregularly distributed. The DMNV revealed a high density of SP-IR terminals and fibers that were mainly concentrated in the periphery. Very few terminals were detected in the LVN. Met-enkephalin immunoreactive (Met-Enk-IR) fibers and terminals showed high density and uniform distribution in the DMNV. Scattered terminals and fibers were observed in the AP, ASP, and NTS (particularly the lateral division). The very few fibers were observed in the LVN surrounded the neuronal cell bodies. The present report is part of a study designed to investigate the interaction between neuropeptides and conventional neurotransmitters under conditions producing motion sickness and in the process of sensory-motor adaptation.

Damelio, F.; Daunton, Nancy G.; Fox, Robert A.



Role of a ?-aminobutryic acid (GABA) receptor mutation in the evolution and spread of Diabrotica virgifera virgifera resistance to cyclodiene insecticides.  


The western corn rootworm, Diabrotica virgifera virgifera, is a damaging pest of cultivated corn that was controlled by applications of cyclodiene insecticides from the late 1940s until resistance evolved ?10 years later. Range expansion from the western plains into eastern USA coincides with resistance development. An alanine to serine amino acid substitution within the Rdl subunit of the gamma-aminobutyric acid (GABA) receptor confers resistance to cyclodiene insecticides in many species. We found that the non-synonymous single nucleotide polymorphism (SNP) G/T at the GABA receptor cDNA position 838 (G/T(838)) of D.?v. virgifera resulted in the alanine to serine change, and the codominant SNP allele T(838) was genetically linked to survival of beetles in aldrin bioassays. A phenotypic gradient of decreasing susceptibility from west to east was correlated with higher frequencies of the resistance-conferring T(838) allele in the eastern-most populations. This pattern exists in opposition to perceived selective pressures since the more eastern and most resistant populations probably experienced reduced exposure. The reasons for the observed distribution are uncertain, but historical records of the range expansion combined with the distribution of susceptible and resistant phenotypes and genotypes provide an opportunity to better understand factors affecting the species' range expansion. PMID:23841833

Wang, H; Coates, B S; Chen, H; Sappington, T W; Guillemaud, T; Siegfried, B D



Effects of yoga on the autonomic nervous system, gamma-aminobutyric-acid, and allostasis in epilepsy, depression, and post-traumatic stress disorder.  


A theory is proposed to explain the benefits of yoga practices in diverse, frequently comorbid medical conditions based on the concept that yoga practices reduce allostatic load in stress response systems such that optimal homeostasis is restored. It is hypothesized that stress induces (1) imbalance of the autonomic nervous system (ANS) with decreased parasympathetic nervous system (PNS) and increased sympathetic nervous system (SNS) activity, (2) underactivity of the gamma amino-butyric acid (GABA) system, the primary inhibitory neurotransmitter system, and (3) increased allostatic load. It is further hypothesized that yoga-based practices (4) correct underactivity of the PNS and GABA systems in part through stimulation of the vagus nerves, the main peripheral pathway of the PNS, and (5) reduce allostatic load. Depression, epilepsy, post traumatic stress disorder (PTSD), and chronic pain exemplify medical conditions that are exacerbated by stress, have low heart rate variability (HRV) and low GABAergic activity, respond to pharmacologic agents that increase activity of the GABA system, and show symptom improvement in response to yoga-based interventions. The observation that treatment resistant cases of epilepsy and depression respond to vagal nerve stimulation corroborates the need to correct PNS underactivity as part of a successful treatment plan in some cases. According to the proposed theory, the decreased PNS and GABAergic activity that underlies stress-related disorders can be corrected by yoga practices resulting in amelioration of disease symptoms. This has far-reaching implications for the integration of yoga-based practices in the treatment of a broad array of disorders exacerbated by stress. PMID:22365651

Streeter, C C; Gerbarg, P L; Saper, R B; Ciraulo, D A; Brown, R P



Muscimol as an ionotropic GABA receptor agonist.  


Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol(®)) and 4-PIOL. PMID:24473816

Johnston, Graham A R



Detection of Reduced GABA Synthesis Following Inhibition of GABA Transaminase Using in Vivo Magnetic Resonance Signal of [13C]GABA C1  

PubMed Central

Previous in vivo magnetic resonance spectroscopy (MRS) studies of gamma-aminobutyric acid (GABA) synthesis have relied on 13C label incorporation into GABA C2 from [1-13C] or [1,6-13C2]glucose. In this study, the [13C]GABA C1 signal at 182.3 ppm in the carboxylic/amide spectral region of localized in vivo 13C spectra was detected. GABA-transaminase of rat brain was inhibited by administration of gabaculine after pre-labeling of GABA C1 and its metabolic precursors with exogenous [2,5-13C2]glucose. A subsequent isotope chase experiment was performed by infusing unlabeled glucose, which revealed a markedly slow change in the labeling of GABA C1 accompanying the blockade of the GABA shunt. This slow labeling of GABA at elevated GABA concentration was attributed to the relatively small intercompartmental GABA-glutamine cycling flux that constitutes the main route of 13C label loss during the isotope chase. Because this study showed that using low RF power broadband stochastic proton decoupling is feasible at very high field strength, it has important implications for the development of carboxylic/amide 13C MRS methods to study brain metabolism and neurotransmission in human subjects at high magnetic fields. PMID:19540876

Yang, Jehoon; Johnson, Christopher; Shen, Jun



GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications  

E-print Network

Review GABA transporters in the mammalian cerebral cortex: localization, development-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the mammalian cerebral cortex, are regulated-1 and -3 are expressed in the cerebral cortex. Studies of the cortical distribution, cellular

Sandini, Giulio


Genetics Home Reference: Succinic semialdehyde dehydrogenase deficiency  


... The ALDH5A1 gene provides instructions for producing the succinic semialdehyde dehydrogenase enzyme. This enzyme is involved in the breakdown of a chemical that transmits signals in the brain (neurotransmitter) called gamma-amino butyric acid (GABA). The primary role of GABA is to ...


GABA (?-aminobutyric acid), a non-protein amino acid counters the ?-adrenergic cascade-activated oncogenic signaling in pancreatic cancer: a review of experimental evidence.  


GABA is a bioactive constituent of fruits, vegetables, cereals and is believed to play a role in defense against stress in plants. In animals, it acts as an inhibitory neurotransmitter in brain while also expressed in non-neuronal cells. Studies have implicated the regulator of fight or flight stress responses, ?-AR signaling cascade, as mediators of cancer growth and progression in in vitro and in vivo models of pancreatic malignancies. Pancreatic cancer is the fourth leading cause of cancer mortality in western countries. This malignancy is generally unresponsive to conventional radio- and chemotherapy, resulting in mortality rate near 100% within 6 months of diagnosis. We review a series of experiments from our laboratory and those of others examining the contribution of this signaling network to pancreatic and other human malignancies. Stimulation of the ?-adrenergic receptor by lifestyle and environmental factors, as well as a pre-existing risk of neoplasm, activates downstream effector molecules that lead to pro-oncogenic signaling and thereby aid cancer growth. GABAergic signaling mediated by the serpentine receptor GABA(B) acts as an antagonist to ?-adrenergic cascade by intercepting adenylyl cyclase. These evidences enhance the pharmacological value of human diets rich in GABA for use as an adjuvant to standard therapies. PMID:21805621

Al-Wadei, Hussein A N; Ullah, Mohammad F; Al-Wadei, Mohammed



Development and Validation of a HPTLC Method for Simultaneous Estimation of L-Glutamic Acid and ?-Aminobutyric Acid in Mice Brain.  


A new robust, simple and economic high performance thin layer chromatographic method was developed for simultaneous estimation of L-glutamic acid and ?-amino butyric acid in brain homogenate. The high performance thin layer chromatographic separation of these amino acid was achieved using n-butanol:glacial acetic acid:water (22:3:5 v/v/v) as mobile phase and ninhydrin as a derivatising agent. Quantitation of the method was achieved by densitometric method at 550 nm over the concentration range of 10-100 ng/spot. This method showed good separation of amino acids in the brain homogenate with Rf value of L-glutamic acid and ?-amino butyric acid as 21.67±0.58 and 33.67±0.58, respectively. The limit of detection and limit of quantification for L-glutamic acid was found to be 10 and 20 ng and for ?-amino butyric acid it was 4 and 10 ng, respectively. The method was also validated in terms of accuracy, precision and repeatability. The developed method was found to be precise and accurate with good reproducibility and shows promising applicability for studying pathological status of disease and therapeutic significance of drug treatment. PMID:24591747

Sancheti, J S; Shaikh, M F; Khatwani, P F; Kulkarni, Savita R; Sathaye, Sadhana



Excitatory actions of gaba during development: the nature of the nurture  

Microsoft Academic Search

In the immature brain, GABA (?-aminobutyric acid) is excitatory, and GABA-releasing synapses are formed before glutamatergic contacts in a wide range of species and structures. GABA becomes inhibitory by the delayed expression of a chloride exporter, leading to a negative shift in the reversal potential for choride ions. I propose that this mechanism provides a solution to the problem of

Yehezkel Ben-Ari



Prediction of GABA A receptor proteins using the concept of Chou's pseudo-amino acid composition and support vector machine  

Microsoft Academic Search

The amino acid gamma-aminobutyric-acid receptors (GABAARs) belong to the ligand-gated ion channels (LGICs) superfamily. GABAARs are highly diverse in the central nervous system. These channels play a key role in regulating behavior. As a result, the prediction of GABAARs from the amino acid sequence would be helpful for research on these receptors. We have developed a method to predict these

Hassan Mohabatkar; Majid Mohammad Beigi; Abolghasem Esmaeili



Stimulation of GABA release by scorpion venom in an isolated synapse in the crayfish ( Astacus leptodactylus)  

Microsoft Academic Search

Effects of various types of scorpion venom on gamma-aminobutyric acid (GABA) release were studied in an isolated synapse in the crayfish. Post-synaptic GABA-induced currents were recorded to monitor the GABA release from the pre-synaptic site. In 20mM tetraethylammonium (TEA) chloride solution the GABA-induced currents increased 71%. Exposing the preparations to Leiurus quinquestriatus hebraeus, Leiurus quinquestriatus quinquestriatus or Tityus serrulatus venom

Nuhan Purali



Distribution of 3H-GABA uptake sites in the nematode Ascaris  

SciTech Connect

The distribution of uptake sites for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the nematode Ascaris suum was examined by autoradiography of 3H-GABA uptake. Single neural processes in both the ventral and dorsal nerve cords were labeled with 3H-GABA. Serial section analysis identified the cells of origin of these processes as the RMEV-like and RMED-like neurons. These cells belong to a set of four neurons in the nerve ring, all of which are labeled by 3H-GABA. 3H-GABA labeling of at least two other sets of cephalic neurons was seen. One of these pairs consists of medium-sized lateral ganglia neurons, located at the level of the amphid commissure bundle. A second pair is located in the lateral ganglia at the level of the deirid commissure bundle. The position and size of these lateral ganglia cells suggest that they are the GABA-immunoreactive lateral ganglia cells frequently seen in whole-mount immunocytochemical preparations. Four neuronal cell bodies located in the retrovesicular ganglion were also labeled with 3H-GABA. These cells, which are probably cholinergic excitatory motor neurons, do not contain detectable GABA-like immunoreactivity. Heavy labeling of muscle cells was also observed. The ventral and dorsal nerve cord inhibitory motor neurons, which are known to contain GABA-like immunoreactivity, were not labeled above background with 3H-GABA. Together with the experiments reported previously, these results define three classes of GABA-associated neurons in Ascaris: (1) neurons that contain endogenous GABA and possess a GABA uptake system; (2) neurons that contain endogenous GABA, but that either lack a GABA uptake system or possess a GABA uptake system of low activity; (3) neurons that possess a GABA uptake system, but that lack endogenous GABA.

Guastella, J.; Stretton, A.O. (University of Wisconsin, Madison (USA))



GABA Promotes Human ?-Cell Proliferation and Modulates Glucose Homeostasis.  


?-Aminobutyric acid (GABA) exerts protective and regenerative effects on mouse islet ?-cells. However, in humans it is unknown whether it can increase ?-cell mass and improve glucose homeostasis. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-? mice with streptozotocin-induced diabetes. GABA treatment increased grafted ?-cell proliferation, while decreasing apoptosis, leading to enhanced ?-cell mass. This was associated with increased circulating human insulin and reduced glucagon levels. Importantly, GABA administration lowered blood glucose levels and improved glucose excursion rates. We investigated GABA receptor expression and signaling mechanisms. In human islets, GABA activated a calcium-dependent signaling pathway through both GABA A receptor and GABA B receptor. This activated the phosphatidylinositol 3-kinase-Akt and CREB-IRS-2 signaling pathways that convey GABA signals responsible for ?-cell proliferation and survival. Our findings suggest that GABA regulates human ?-cell mass and may be beneficial for the treatment of diabetes or improvement of islet transplantation. PMID:25008178

Purwana, Indri; Zheng, Juan; Li, Xiaoming; Deurloo, Marielle; Son, Dong Ok; Zhang, Zhaoyun; Liang, Christie; Shen, Eddie; Tadkase, Akshaya; Feng, Zhong-Ping; Li, Yiming; Hasilo, Craig; Paraskevas, Steven; Bortell, Rita; Greiner, Dale L; Atkinson, Mark; Prud'homme, Gerald J; Wang, Qinghua



Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition.  


GABA is the major inhibitory transmitter in the brain and is released not only from a subset of neurons but also from glia. Although neuronal GABA is well known to be synthesized by glutamic acid decarboxylase (GAD), the source of glial GABA is unknown. After estimating the concentration of GABA in Bergmann glia to be around 5-10 mm by immunogold electron microscopy, we demonstrate that GABA production in glia requires MAOB, a key enzyme in the putrescine degradation pathway. In cultured cerebellar glia, both Ca(2+)-induced and tonic GABA release are significantly reduced by both gene silencing of MAOB and the MAOB inhibitor selegiline. In the cerebellum and striatum of adult mice, general gene silencing, knock out of MAOB or selegiline treatment resulted in elimination of tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial-specific rescue of MAOB resulted in complete rescue of tonic GABA currents. Our results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via bestrophin 1 (Best1) channel to mediate tonic inhibition in the brain. PMID:25239459

Yoon, Bo-Eun; Woo, Junsung; Chun, Ye-Eun; Chun, Heejung; Jo, Seonmi; Bae, Jin Young; An, Heeyoung; Min, Joo Ok; Oh, Soo-Jin; Han, Kyung-Seok; Kim, Hye Yun; Kim, Taekeun; Kim, Young Soo; Bae, Yong Chul; Lee, C Justin



Long-Lasting Facilitation of 4Aminon(2,3-3H)butyric Acid ((3H)GABA) Release from Rat Hippocampal Slices by Nicotinic Receptor Activation1  

Microsoft Academic Search

In this study we explored the effect of the stimulation of nico- tinic acetylcholine receptors located on interneurons by mea- suring 4-amino-n-(2,3-3H)butyric acid ((3H)GABA) release and monitoring (Ca 21)i in superfused hippocampal slices. In the presence of 6-cyano-7-nitroquinoxaline-2,3-dione, (6)-2-ami- no-5-phosphonopentanoic acid, and atropine, i.e., under the blockade of N-methyl-D-aspartate and non-N-methyl-D-aspar- tate glutamate and muscarinic receptors, nicotine did not alter



Incorporation of Different Bridge Length Linkers in Enzyme and Its Use in the Preparation of Enzyme Conjugates for Immunoassay  

Microsoft Academic Search

An enzyme horseradish peroxidase (HRP), as a starting material, has been used to introduce different bridge length linkers, and its use in the preparation of enzyme conjugates for immunoassay is described. HRP was conjugated to adipic acid dihydrazide (ADH), gamma amino butyric acid (GABA), followed by ADH and 6?amino caproic acid (6ACA) followed by ADH. The different bridge length linkers?incorporated

Tulsidas G. Shrivastav



Up-regulation of GABA(B) receptors by chronic administration of the GABA(B) receptor antagonist SCH 50,911.  


Chronic treatment of mice with the specific gamma-aminobutyric acid(B) (GABA(B)) receptor antagonist (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50,911) increased both the number of GABA(B) receptors in the whole brain (measured as [3H]CGP 54626 [S-(R,R)]-3-[[1-(3,4-dichlorophenyl)amino]-2-hydroxypropyl](cyclohexylmethyl)phosphinic acid hydrochloride binding) and the ability of baclofen to activate GABA(B) receptor coupled G-protein (measured as % reduction of the EC50 of baclofen to activate [35S]GTP(gamma)S binding). The results indicate that persistent blockade of GABA(B) receptors leads to their compensatory up-regulation and suggest that GABA(B) receptors are tonically activated by endogenous GABA. PMID:15893746

Pibiri, Fabio; Carboni, Giovanni; Carai, Mauro A M; Gessa, Gian Luigi; Castelli, M Paola



GABA Predicts Time Perception  

PubMed Central

Our perception of time constrains our experience of the world and exerts a pivotal influence over a myriad array of cognitive and motor functions. There is emerging evidence that the perceived duration of subsecond intervals is driven by sensory-specific neural activity in human and nonhuman animals, but the mechanisms underlying individual differences in time perception remain elusive. We tested the hypothesis that elevated visual cortex GABA impairs the coding of particular visual stimuli, resulting in a dampening of visual processing and concomitant positive time-order error (relative underestimation) in the perceived duration of subsecond visual intervals. Participants completed psychophysical tasks measuring visual interval discrimination and temporal reproduction and we measured in vivo resting state GABA in visual cortex using magnetic resonance spectroscopy. Time-order error selectively correlated with GABA concentrations in visual cortex, with elevated GABA associated with a rightward horizontal shift in psychometric functions, reflecting a positive time-order error (relative underestimation). These results demonstrate anatomical, neurochemical, and task specificity and suggest that visual cortex GABA contributes to individual differences in time perception. PMID:24647956

Russo, Sonia; Near, Jamie; Stagg, Charlotte J.; Cohen Kadosh, Roi



Glutamate Uptake Triggers Transporter-Mediated GABA Release from Astrocytes  

PubMed Central

Background Glutamate (Glu) and ?-aminobutyric acid (GABA) transporters play important roles in regulating neuronal activity. Glu is removed from the extracellular space dominantly by glial transporters. In contrast, GABA is mainly taken up by neurons. However, the glial GABA transporter subtypes share their localization with the Glu transporters and their expression is confined to the same subpopulation of astrocytes, raising the possibility of cooperation between Glu and GABA transport processes. Methodology/Principal Findings Here we used diverse biological models both in vitro and in vivo to explore the interplay between these processes. We found that removal of Glu by astrocytic transporters triggers an elevation in the extracellular level of GABA. This coupling between excitatory and inhibitory signaling was found to be independent of Glu receptor-mediated depolarization, external presence of Ca2+ and glutamate decarboxylase activity. It was abolished in the presence of non-transportable blockers of glial Glu or GABA transporters, suggesting that the concerted action of these transporters underlies the process. Conclusions/Significance Our results suggest that activation of Glu transporters results in GABA release through reversal of glial GABA transporters. This transporter-mediated interplay represents a direct link between inhibitory and excitatory neurotransmission and may function as a negative feedback combating intense excitation in pathological conditions such as epilepsy or ischemia. PMID:19777062

Heja, Laszlo; Barabas, Peter; Nyitrai, Gabriella; Kekesi, Katalin A.; Lasztoczi, Balint; Toke, Orsolya; Tarkanyi, Gabor; Madsen, Karsten; Schousboe, Arne; Dobolyi, Arpad; Palkovits, Miklos; Kardos, Julianna



Relative efficacies of 1,4-diazepines on GABA-stimulated chloride influx in rat brain vesicles  

SciTech Connect

The effects of 1,4-diazepines with two annelated heterocycles (brotizolam (WE 941), ciclotizolam (WE 973) and WE 1008) on gamma-aminobutyric acid (GABA)-stimulated chloride influx into rat brain membrane vesicles were examined. Brotizolam enhanced GABA-stimulated /sup 36/Cl/sup /minus// influx, while ciclotizolam and WE 1008 showed only a small enhancement of GABA-stimulated /sup 36/Cl/sup /minus// uptake. Brotizolam resulted in a left shift of the GABA dose response curve at lower concentrations of GABA, while at higher concentrations of GABA, brotizolam caused a reduction of the maximal response. The enhancement of GABA-stimulated /sup 36/Cl/sup /minus// uptake by brotizolam was antagonized by Ro 15-1788. At higher concentration of GABA (300 /mu/M), brotizolam inhibited GABA-stimulated /sup 36/Cl/sup /minus// uptake in a dose dependent manner and Ro 15-1788 failed to antagonize this effect.

Ikeda, Masaaki; Weber, K.H.; Bechtel, W.D.; Malatynska, E.; Yamamura, H.I.



Bioactivity-guided isolation of GABA(A) receptor modulating constituents from the rhizomes of Actaea racemosa.  


Black cohosh (Actaea racemosa) is a frequently used herbal remedy for the treatment of mild climacteric symptoms. In the present study, the modulation of ?-aminobutryic acid (GABA)-induced chloride currents (I(GABA)) through GABA type A (GABA(A)) receptors by black cohosh extracts and isolated compounds was investigated. GABA(A) receptors, consisting of ?(1), ?(2), and ?(2S) subunits, were expressed in Xenopus laevis oocytes, and potentiation of I(GABA) was measured using the two-microelectrode voltage clamp technique. In a bioactivity-guided isolation procedure the positive modulation of I(GABA) could be restricted to the plant terpenoid fractions, resulting in the isolation of 11 cycloartane glycosides, of which four significantly (p < 0.05) enhanced I(GABA). The most efficient effect was observed for 23-O-acetylshengmanol 3-O-?-d-xylopyranoside (4, 100 ?M), enhancing I(GABA) by 1692 ± 201%, while actein (1), cimigenol 3-O-?-d-xylopyranoside (6), and 25-O-acetylcimigenol 3-O-?-l-arabinopyranoside (8) were significantly less active. In the absence of GABA, only 4 induced small (not exceeding 1% of I(GABA-max)) chloride inward currents through GABA(A) receptors. It is hypothesized that the established positive allosteric modulation of GABA(A) receptors may contribute to beneficial effects of black cohosh extracts in the treatment of climacteric symptoms. PMID:21082802

Cicek, Serhat S; Khom, Sophia; Taferner, Barbara; Hering, Steffen; Stuppner, Hermann



Presynaptic Ionotropic GABA Receptors  

Microsoft Academic Search

Presynaptic autoreceptors modulate the release of GABA from terminals of inhibitory interneurons. We have shown that in rodent\\u000a hippocampal CA3 this feedback involves the activation of ionotropic GABAAR which suppress further release in acutely prepared tissue. Under conditions of different EC1, the same feedback might be positively coupled to release, giving rise to bursts of IPSCs after an initial (large)

Nikolai Axmacher; Kristin Hartmann; Andreas Draguhn


Neurobiology of echolocation in bats Cynthia F Moss  

E-print Network

/inhibitory contralateral/ipsilateral inputs FM frequency modulated GABA g-amino butyric acid IC inferior colliculus ILD by the bat to probe the environment directly influence the information available to its acoustic imaging system. In turn, the bat's auditory representation of the environment guides adaptive motor behaviors

Moss, Cynthia


Oscillatory activity in the medial prefrontal cortex and nucleus accumbens correlates with impulsivity and reward outcome  

E-print Network

levels of impulsivity on the 5-CSRTT (i.e., repeated failures in 63 action restraint, or waiting impulsivity) show abnormal dopamine (DA) and ?-amino-butyric acid 64 (GABA) function in the NAcb [10,34–37] and manipulations of the DA innervation...

Donnelly, Nicholas A.; Holtzman, Tahl; Rich, P. Dylan; Nevado-Holgado, Alejo J.; Fernando, Anushka B. P.; Dijck, Gert Van; Holzhammer, Tobias; Paul, Oliver; Ruther, Patrick; Paulsen, Ole; Robbins, Trevor W.; Dalley, Jeffrey W.



Influence of gender and brain region on neurosteroid modulation of GABA responses in rats  

Microsoft Academic Search

Neuroactive steroid derivatives of progesterone, testosterone and glucocorticoids can alter physiological responses to ?-aminobutyric acid (GABA), apparently through direct, non-steroid receptor mechanisms. The present study examined gender-related differences and regional variations in the ability of tetrahydrodeoxycorticosterone (THDOC), 3?-hydroxy-5?-pregnan-20-one (3?-5?-THP, tetrahydroprogesterone), androsterone, and dihydroandrosterone (DHA) to alter physiological GABA responses. Steroid modulation of GABA-activated 36chloride influx into microsac preparations from cortex,

Marlene A. Wilson; Rosemary Biscardi



GABA in regulation of communicative activity and sexual motivation of male mice with different psychoemotional status.  


We studied the effects of drugs modulating GABA content in the brain on communicative activity and sexual motivation of male mice. The effects of the drug depended on animal genotype and initial psychoemotional status. Aminooxyacetic acid elevating GABA content did not modulate communicative activity of intact males, reduced it in aggressive animals, restored in anxious animals, and promoted exhaustion of sexual motivation in anxious animals. Thiosemicarbazide reducing GABA level produced an anxiogenic effect and destabilized sexual motivation in intact males. PMID:17970208

Amikishieva, A V



Zinc-Induced Collapse of Augmented Inhibition by GABA in a Temporal Lobe Epilepsy Model  

Microsoft Academic Search

In the kindling model of temporal lobe epilepsy, several physiological indicators of inhibition by gamma-aminobutyric acid (GABA) in the hippocampal dentate gyrus are consistent with an augmented, rather than a diminished, inhibition. In brain slices obtained from epileptic (kindled) rats, the excitatory drive onto inhibitory interneurons was increased and was paralleled by a reduction in the presynaptic autoinhibition of GABA

Eberhard H. Buhl; Thomas S. Otis; Istvan Mody



Taurine-like GABA aminotransferase inhibitors prevent rabbit brain slices against oxygen–glucose deprivation-induced damage  

Microsoft Academic Search

The activation of the GABAergic system has been shown to protect brain tissues against the damage that occurs after cerebral\\u000a ischaemia. On the other hand, the taurine analogues (±)Piperidine-3-sulphonic- (PSA), 2-aminoethane phosphonic- (AEP), 2-(N-acetylamino) cyclohexane sulfonic-acids (ATAHS) and 2-aminobenzene sulfonate-acids (ANSA) have been reported to block GABA\\u000a metabolism by inhibiting rabbit brain GABA aminotransferase and to increase GABA content in

Lorenzo Ricci; Massimo Valoti; Giampietro Sgaragli; Maria Frosini


Downregulation of GABA[Subscript A] Receptor Protein Subunits a6, ß2, d, e, ?2, ?, and ?2 in Superior Frontal Cortex of Subjects with Autism  

ERIC Educational Resources Information Center

We measured protein and mRNA levels for nine gamma-aminobutyric acid A (GABA[subscript A]) receptor subunits in three brain regions (cerebellum, superior frontal cortex, and parietal cortex) in subjects with autism versus matched controls. We observed changes in mRNA for a number of GABA[subscript A] and GABA[subscript B] subunits and overall…

Fatemi, S. Hossein; Reutiman, Teri J.; Folsom, Timothy D.; Rustan, Oyvind G.; Rooney, Robert J.; Thuras, Paul D.



AtGAT1, a High Affinity Transporter for -Aminobutyric Acid in Arabidopsis thaliana*  

E-print Network

AtGAT1, a High Affinity Transporter for -Aminobutyric Acid in Arabidopsis thaliana* Received, high affinity -aminobutyric acid (GABA) trans- porter. In addition to GABA, other -aminofatty acids conditions of elevated GABA concentrations such as wounding or senescence. -Aminobutyric acid (GABA)3

Eskandari, Sepehr


Co-release of acetylcholine and GABA by the starburst amacrine cells.  


Rabbit retinas were isolated from the eye and maintained in vitro. When they were incubated for 60 min in the presence of 3H-GABA, subsequent autoradiography showed radioactivity to be present primarily in amacrine cells. Under these conditions, most of the radioactivity contained in the retinas remained in the chemical form of GABA. Autoradiography and immunohistochemistry of alternate sections showed the amacrine cells that accumulate 3H-GABA to be the same cells that contain endogenous GABA immunoreactivity. These include the starburst cells, the indoleamine-accumulating cells, and other, as yet unidentified amacrine cells. The localization confirms previous immunohistochemical findings. When retinas containing 3H-GABA were expressed to elevated concentrations of K+, their content of 3H-GABA decreased. Autoradiography showed a reduced 3H-GABA content in all of the cells that contained 3H-GABA. Since those include the starburst cells, previously shown to be cholinergic, the finding demonstrates that the starburst cells release both ACh and GABA. Retinas simultaneously labeled with 14C-GABA and 3H-ACh were superfused, and the release of radioactive compounds from the retina was studied. Depolarization by elevated K+ caused an increased recovery of both ACh and GABA in the superfusate, but the predominant mechanisms of their release appeared to be different. The stimulated release of ACh was entirely Ca2+ dependent, while the release of radioactivity originating from GABA was much less so. A concentration-dependent counterflux (homoexchange) of intracellular GABA was demonstrated by raising the extracellular concentration of GABA (or nipecotic acid). These results suggest that a large outward flux of GABA occurs via the GABA transporter, probably by the potential-sensitive mechanism studied by Schwartz (1982, 1987). Stimulation of double-labeled retinas by flashing light or moving bars always increased the release of ACh, and the release was entirely dependent on the presence of extracellular Ca2+. Stimulation with light never caused a detectable release of GABA. This was unexpected, since the two neurotransmitters are present in the same amacrine cells: stimulation adequate to release one neurotransmitter should release both.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:1556600

O'Malley, D M; Sandell, J H; Masland, R H



Knockout of GAD65 has major impact on synaptic GABA synthesized from astrocyte-derived glutamine  

PubMed Central

?-Aminobutyric acid (GABA) synthesis from glutamate is catalyzed by glutamate decarboxylase (GAD) of which two isoforms, GAD65 and GAD67, have been identified. The GAD65 has repeatedly been shown to be important during intensified synaptic activity. To specifically elucidate the significance of GAD65 for maintenance of the highly compartmentalized intracellular and intercellular GABA homeostasis, GAD65 knockout and corresponding wild-type mice were injected with [1-13C]glucose and the astrocyte-specific substrate [1,2-13C]acetate. Synthesis of GABA from glutamine in the GABAergic synapses was further investigated in GAD65 knockout and wild-type mice using [1,2-13C]acetate and in some cases ?-vinylGABA (GVG, Vigabatrin), an inhibitor of GABA degradation. A detailed metabolic mapping was obtained by nuclear magnetic resonance (NMR) spectroscopic analysis of tissue extracts of cerebral cortex and hippocampus. The GABA content in both brain regions was reduced by ?20%. Moreover, it was revealed that GAD65 is crucial for maintenance of biosynthesis of synaptic GABA particularly by direct synthesis from astrocytic glutamine via glutamate. The GAD67 was found to be important for synthesis of GABA from glutamine both via direct synthesis and via a pathway involving mitochondrial metabolism. Furthermore, a severe neuronal hypometabolism, involving glycolysis and tricarboxylic acid (TCA) cycle activity, was observed in cerebral cortex of GAD65 knockout mice. PMID:20664610

Walls, Anne B; Eyjolfsson, Elvar M; Smeland, Olav B; Nilsen, Linn Hege; Schousboe, Inger; Schousboe, Arne; Sonnewald, Ursula; Waagepetersen, Helle S



[Antihypoxic properties of GABA-containing vitamin derivatives].  


The antihypoxic properties of GABA-containing vitamin derivatives (pyridoxalphosphate-GABA, picamilone, pantogam, sodium homopantothenate) as compared with GABA were studied. All agents were found to increase mouse life expectancy under hypoxia in contrast to GABA. PMID:2707423

Karaev, A L; Kovler, M A; Avakumov, V M; Kopelevich, V M; Bulanova, L N



Microperfusion of 3-MPA into the brain augments GABA  

PubMed Central

In vivo effects of microperfusion of a GABA synthesis inhibitor (3-MPA) into the striatum and hippocampus on amino acid concentrations and electrical neuronal activity were investigated. Paradoxical elevations in GABA in the striatum (5-fold in anesthetized and 50-fold in awake rats) and hippocampus (2-fold in anesthetized and 15-fold in awake rats) were documented under steady-state concentrations of 3-MPA along with expected increases in glutamate (a 15-fold increase and a 250-fold increase in the striatum of anesthetized and awake rats, respectively; a 7-fold increase and a 25-fold increase in the hippocampus of anesthetized and awake rats, respectively). There was no clear epileptiform or seizure activity. Explanations for the paradoxical increase in GABA are offered, and emphasis is placed on the dependency of disinhibition on the model in which its effects are studied as well as on the prevailing level of activation of the probed network. PMID:24094842

Mayer, Andrew P.; Osorio, Ivan; Lunte, Craig E.



Abundant GABAergic innervation of rat posterior pituitary revealed by inhibition of GABA-transaminase.  


An antibody against gamma-aminobutyric acid (GABA) was used to identify GABAergic elements immunocytochemically in the rat posterior pituitary. In order to increase the intracellular concentration of GABA, rats were treated with the GABA-transaminase inhibitor gamma-vinyl-GABA (GVG). Light-microscopic observations of Vibratome and semithin sections revealed the presence of numerous immunoreactive nerve fibers throughout the neural lobe; the mean number and length of these fibers increased by 90% after GVG treatment. Electron microscopy demonstrated the immunostained axons to be of small diameter. The reaction product was confined to small vesicles. No immunostaining occurred in pituicytes. The richness of the GABAergic innervation of the neural lobe contrasts with previous reports using antibodies against glutamate decarboxylase and supports the idea that GABA participates in the presynaptic control of neurosecretion. PMID:3342443

Brüstle, O; Pilgrim, C; Gaymann, W; Reisert, I



GABA-shunt enzymes activity in GH3 cells with reduced level of PMCA2 or PMCA3 isoform  

SciTech Connect

Highlights: {yields} Suppression of PMCA2 or PMCA3 slows down proliferation of GH3 cells. {yields} PMCA2 suppression lowers the activity of GABA-shunt enzymes. {yields} PMCA3 suppression increases the expression of glutamate decarboxylase 65. {yields} PMCA2 and PMCA3 function appears to be linked to regulation of GABA metabolism. -- Abstract: GABA ({gamma}-aminobutyric acid) is important neurotransmitter and regulator of endocrine functions. Its metabolism involves three enzymes: glutamate decarboxylase (GAD65 and GAD67), GABA aminotransferase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH). As many cellular processes GABA turnover can depend on calcium homeostasis, which is maintained by plasma membrane calcium ATPases (PMCAs). In excitable cells PMCA2 and PMCA3 isoforms are particularly important. In this study we focused on GABA-metabolizing enzymes expression and activity in rat anterior pituitary GH3 cells with suppressed expression of PMCA2 or PMCA3. We observed that PMCA3-reduced cells have increased GAD65 expression. Suppression of PMCA2 caused a decrease in total GAD and GABA-T activity. These results indicate that PMCA2 and PMCA3 presence may be an important regulatory factor in GABA metabolism. Results suggest that PMCA2 and PMCA3 function is rather related to regulation of GABA synthesis and degradation than supplying cells with metabolites, which can be potentially energetic source.

Kowalski, Antoni, E-mail: [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland)] [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland); Zylinska, Ludmila, E-mail: [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland)] [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland); Boczek, Tomasz, E-mail: [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland)] [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland); Rebas, Elzbieta, E-mail: [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland)] [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland)



Temperature dependence and GABA modulation of (TH)triazolam binding in the rat brain  

SciTech Connect

The hypnotic triazolam (TZ), a triazolobenzodiazepine displays a short physiological half life and has been used for the treatment of insomnia related to anxiety states. The authors major objectives were the direct measurement of the temperature dependence and the gamma-aminobutyric acid (GABA) effect of (TH)TZ binding in the rat brain. Saturation studies showed a shift to lower affinity with increasing temperatures (K/sub d/ = 0.27 +/- 08 nM at 0C; K/sub d/ = 1.96 +/- 0.85 nM at 37C) while the B/sub max/ values remained unchanged (1220 +/- 176 fmoles/mg protein at 0C and 1160 +/- 383 fmoles/mg protein at 37C). Saturation studies of (TH)TZ binding in the presence or absence of GABA (100 M) showed a GABA-shift. At 0C the K/sub d/ values were (K/sub d/ = 0.24 +/- 0.03 nM/-GABA; K/sub d/ = 0.16 +/- 0.04/+GABA) and at 37C the K/sub d/ values were (K/sub d/ = 1.84 +/- 0.44 nM/-GABA; K/sub d/ = 0.95 +/- 0.29 nM/+GABA). In contrast to reported literature, the authors findings show that TZ interacts with benzodiazepine receptors with a temperature dependence and GABA-shift consistent with predicted behavior for benzodiazepine agonists. 20 references, 3 tables.

Earle, M.E.; Concas, A.; Wamsley, J.K.; Yamamura, H.I.



Anterior Insula GABA Levels Correlate with Emotional Aspects of Empathy: A Proton Magnetic Resonance Spectroscopy Study  

PubMed Central

Background: Empathy is a multidimensional construct referring to the capacity to understand and share the emotional and affective states of another person. Cerebral ?-aminobutyric acid (GABA)-ergic levels are associated with a variety of neurological and psychiatric disorders. However, the role of the GABA system in different dimensions of empathy has not been investigated. Materials and Methods: Thirty-two right-handed healthy volunteers took part in this study. We used proton magnetic resonance spectroscopy to determine GABA concentrations in the anterior insula (AI) and the anterior cingulate cortex (ACC) and to examine the relationship between the GABA concentrations and the subcomponents of empathy evaluated by the Interpersonal Reactivity Index (IRI). Result: Pearson correlation analyses (two-tailed) showed that AI GABA was significantly associated with the empathy concern score (r?=?0.584, p<0.05) and the personal distress score (r?=?0.538, p<0.05) but not significantly associated with other empathy subscales. No significant correlation was found between ACC GABA and empathy subscores. Conclusion: Left AI GABA was positively correlated with the emotional aspects of empathy. These preliminary findings call into question whether AI GABA alterations might predict empathy dysfunction in major psychiatric disorders such as autism and schizophrenia, which have been described as deficits in emotional empathic abilities. PMID:25419976

Dong, Fang; Chen, Luguang; Zheng, Li; Guo, Xiuyan; Li, Jianqi



Effect of GABA, a Bacterial Metabolite, on Pseudomonas fluorescens Surface Properties and Cytotoxicity.  


Different bacterial species and, particularly Pseudomonas fluorescens, can produce gamma-aminobutyric acid (GABA) and express GABA-binding proteins. In this study, we investigated the effect of GABA on the virulence and biofilm formation activity of different strains of P. fluorescens. Exposure of a psychotropic strain of P. fluorescens (MF37) to GABA (10-5 M) increased its necrotic-like activity on eukaryotic (glial) cells, but reduced its apoptotic effect. Conversely, muscimol and bicuculline, the selective agonist and antagonist of eukaryote GABAA receptors, respectively, were ineffective. P. fluorescens MF37 did not produce biosurfactants, and its caseinase, esterase, amylase, hemolytic activity or pyoverdine productions were unchanged. In contrast, the effect of GABA was associated to rearrangements of the lipopolysaccharide (LPS) structure, particularly in the lipid A region. The surface hydrophobicity of MF37 was marginally modified, and GABA reduced its biofilm formation activity on PVC, but not on glass, although the initial adhesion was increased. Five other P. fluorescens strains were studied, and only one, MFP05, a strain isolated from human skin, showed structural differences of biofilm maturation after exposure to GABA. These results reveal that GABA can regulate the LPS structure and cytotoxicity of P. fluorescens, but that this property is specific to some strains. PMID:23743829

Dagorn, Audrey; Chapalain, Annelise; Mijouin, Lily; Hillion, Mélanie; Duclairoir-Poc, Cécile; Chevalier, Sylvie; Taupin, Laure; Orange, Nicole; Feuilloley, Marc G J



Activity-dependent transport of GABA analogues into specific cell types demonstrated at high resolution using a novel immunocytochemical strategy.  


We have raised antisera against the GABA analogues gamma-vinyl GABA, diaminobutyric acid and gabaculine. These analogues are thought to be substrates for high-affinity GABA transporters. Retinae were exposed to micromolar concentrations of these analogues in the presence or absence of uptake inhibitors and then fixed and processed for immunocytochemistry at the light and electron microscopic levels. Immunolabelling for gamma-vinyl GABA revealed specific labelling of GABAergic amacrine cells and displaced amacrine cells in retinae of rabbits, cats, chickens, fish and a monkey. GABA-containing horizontal cells of cat and monkey retinae failed to exhibit labelling for gamma-vinyl GABA, suggesting that they lacked an uptake system for this molecule. In light-adapted fish, gamma-vinyl GABA was readily detected in H1 horizontal cells; similar labelling was also observed in light-adapted chicken retinae. The pattern of labelling in the fish and chicken retinae was modified by dark adaptation, when labelling was greatly reduced in the horizontal cells, indicating the activity dependence of GABA (analogue) transport. Intraperitoneal injection of gamma-vinyl GABA into rats resulted in its transport across the blood-brain barrier and subsequent uptake into populations of GABAergic neurons. The other analogues investigated in this study exhibited different patterns of transport; gabaculine was taken up into glial cells, whilst diaminobutyric acid was taken up into neurons, glial cells and retinal pigment epithelia. Thus, these analogues are probably substrates for different GABA transporters. We conclude that immunocytochemical detection of the high-affinity uptake of gamma-vinyl GABA permits the identification of GABAergic neurons which are actively transporting GABA, and suggest that this novel methodology will be a useful tool in rapidly assessing the recent activity of GABAergic neurons at the cellular level. PMID:8809830

Pow, D V; Baldridge, W; Crook, D K



The Memory-Impairing Effects of Septal GABA Receptor Activation Involve GABAergic Septo-Hippocampal Projection Neurons  

ERIC Educational Resources Information Center

Septal infusions of the [gamma]-aminobutyric acid (GABA)[subscript A] agonist muscimol impair memory, and the effect likely involves the hippocampus. GABA[subscript A] receptors are present on the perikarya of cholinergic and GABAergic septo-hippocampal (SH) projections. The current experiments determined whether GABAergic SH projections are…

Krebs-Kraft, Desiree L.; Wheeler, Marina G.; Parent, Marise B.



Focal Uncaging of GABA Reveals a Temporally Defined Role for GABAergic Inhibition during Appetitive Associative Olfactory Conditioning in Honeybees  

ERIC Educational Resources Information Center

Throughout the animal kingdom, the inhibitory neurotransmitter ?-aminobutyric acid (GABA) is a key modulator of physiological processes including learning. With respect to associative learning, the exact time in which GABA interferes with the molecular events of learning has not yet been clearly defined. To address this issue, we used two…

Raccuglia, Davide; Mueller, Uli



GABA metabolism pathway genes, UGA1 and GAD1, regulate replicative lifespan in Saccharomycescerevisiae  

SciTech Connect

Highlights: {yields}We demonstrate that two genes in the yeast GABA metabolism pathway affect aging. {yields} Deletion of the UGA1 or GAD1 genes extends replicative lifespan. {yields} Addition of GABA to wild-type cultures has no effect on lifespan. {yields} Intracellular GABA levels do not differ in longevity mutants and wild-type cells. {yields} Levels of tricarboxylic acid cycle intermediates positively correlate with lifespan. -- Abstract: Many of the genes involved in aging have been identified in organisms ranging from yeast to human. Our previous study showed that deletion of the UGA3 gene-which encodes a zinc-finger transcription factor necessary for {gamma}-aminobutyric acid (GABA)-dependent induction of the UGA1 (GABA aminotransferase), UGA2 (succinate semialdehyde dehydrogenase), and UGA4 (GABA permease) genes-extends replicative lifespan in the budding yeast Saccharomycescerevisiae. Here, we found that deletion of UGA1 lengthened the lifespan, as did deletion of UGA3; in contrast, strains with UGA2 or UGA4 deletions exhibited no lifespan extension. The {Delta}uga1 strain cannot deaminate GABA to succinate semialdehyde. Deletion of GAD1, which encodes the glutamate decarboxylase that converts glutamate into GABA, also increased lifespan. Therefore, two genes in the GABA metabolism pathway, UGA1 and GAD1, were identified as aging genes. Unexpectedly, intracellular GABA levels in mutant cells (except for {Delta}uga2 cells) did not differ from those in wild-type cells. Addition of GABA to culture media, which induces transcription of the UGA structural genes, had no effect on replicative lifespan of wild-type cells. Multivariate analysis of {sup 1}H nuclear magnetic resonance spectra for the whole-cell metabolite levels demonstrated a separation between long-lived and normal-lived strains. Gas chromatography-mass spectrometry analysis of identified metabolites showed that levels of tricarboxylic acid cycle intermediates positively correlated with lifespan extension. These results strongly suggest reduced activity of the GABA-metabolizing enzymes extends lifespan by shifting carbon metabolism toward respiration, as calorie restriction does.

Kamei, Yuka; Tamura, Takayuki [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan)] [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan); Yoshida, Ryo [Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)] [Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan); Ohta, Shinji [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan)] [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan); Fukusaki, Eiichiro [Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)] [Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan); Mukai, Yukio, E-mail: [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan)] [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan)



Anterior cingulate and cerebellar GABA and Glu correlations measured by 1H J-difference spectroscopy  

Microsoft Academic Search

Gamma-aminobutyric acid (GABA) and glutamate (Glu) levels, normalized to total creatine (tCr), were measured in the anterior cingulate and cerebellar vermis in healthy adults (n=19, age=24.6±6.4 years) using 1H MRS at 3 T, and metabolite correlations across regions and subjects were determined. Mean anterior cingulate and cerebellar GABA\\/tCr ratios were 0.31 (0.08) and 0.23 (0.06), respectively, while corresponding Glu levels

Kevin W. Waddell; Parham Zanjanipour; Subechhya Pradhan; Lei Xu; Edward B. Welch; James M. Joers; Peter R. Martin; Malcolm J. Avison; John C. Gore



GABA May Act as a Self-Limiting Trophic Factor at Developing Synapses  

NSDL National Science Digital Library

Early in development, synapses with glycine or γ-aminobutyric acid (GABA)-gated chloride channels exhibit the ability to depolarize postsynaptic cells. As the synapses mature and the gradient of chloride ions across the cell membrane is altered, these neurotransmitters signal an inhibitory response, hyperpolarizing the membrane and decreasing neuronal excitability. Kriegstein and Owens discuss how GABA-stimulated up-regulation of the expression of the potassium chloride cotransporter KCC2 may be the mechanism underlying this synaptic switch.

Arnold R. Kriegstein (Columbia College of Physicians and Surgeons;Department of Neurology and Department of Pathology and at the Center for Neurobiology and Behavior REV); David F. Owens (Columbia College of Physicians and Surgeons;Department of Neurology and Department of Pathology and at the Center for Neurobiology and Behavior REV)



An association study between polymorphisms in five genes in glutamate and GABA pathway and paranoid schizophrenia  

Microsoft Academic Search

Dysfunctions of glutamatergic and GABAergic neurotransmission are two important hypotheses for the pathogenesis of schizophrenia. Thus, genes in the pathway are candidates for schizophrenia susceptibility. Phosphate-activated glutaminase (GLS), glutamine synthetase (GLUL), glutamic acid decarboxylase (GAD), GABA transaminase (ABAT) and succinic semialdehyde dehydrogenase (ALDH5A1) are five primary enzymes in glutamate and GABA synthetic and degradative pathway. In order to investigate the

Boyu Zhang; Yanbo Yuan; Yanbin Jia; Xin Yu; Qi Xu; Yucun Shen; Yan Shen



Synaptic interactions involving acetylcholine, glutamate, and GABA in rat auditory cortex  

Microsoft Academic Search

Using electrophysiological techniques in the in vitro rat auditory cortex, we have examined how spontaneous acetylcholine (ACh) release modifies synaptic potentials mediated by glutamate and ?-aminobutyric acid (GABA). Single stimulus pulses to lower layer VI elicited in layer III a four-component (A-D) extracellular field response involving synaptic potentials mediated by glutamate and GABA. The cholinesterase inhibitor eserine (10–20 µM) or

Raju Metherate; John H. Ashe



Effects of GABA and anxiolytics on the single unit discharge of suprachiasmatic neurons in rat hypothalamic slices.  


The effects of gamma-aminobutyric acid (GABA), muscimol, baclofen and the anxiolytics; diazepam (DZP), flurazepam (FZP) and zopiclone on single-unit neural activities in the suprachiasmatic nucleus (SCN) were investigated using the rat hypothalamic slice preparation. Exposure of the slice to GABA 10(-4) M produced inhibitory responses in 65% of the 49 SCN neurons examined. The threshold concentration of GABA ranged from 10(-6) to 10(-4) M. Neurons responsive to GABA were not found to be restricted to a subdivision of the SCN, but were diffusely distributed throughout the nucleus. DZP, FZP and zopiclone produced responses similar to those of GABA. The inhibitory effects of GABA (10(-5) M) were potentiated by coadministration of DZP (10(-5) M). Muscimol and baclofen (10(-7) M to 10(-4) M) also inhibited SCN neuronal activity in a dose-dependent manner. Bicuculline (10(-5) M-10(-4) M) scarcely affected the baclofen-induced inhibition (1/6) but strongly antagonized the effects of muscimol (6/6), GABA (6/8) and DZP (4/5). These results suggest that the receptors mediating the inhibitory effects of GABA and anxiolytics within the SCN may be GABAA and/or GABAB or GABA-BDZ receptor complex, respectively. PMID:1976421

Liou, S Y; Shibata, S; Albers, H E; Ueki, S



Novel functions of GABA signaling in adult neurogenesis  

PubMed Central

Neurotransmitter gamma-aminobutiric acid (GABA) through ionotropic GABAA and metabotropic GABAB receptors plays key roles in modulating the development, plasticity and function of neuronal networks. GABA is inhibitory in mature neurons but excitatory in immature neurons, neuroblasts and neural stem/progenitor cells (NSCs/NPCs). The switch from excitatory to inhibitory occurs following the development of glutamatergic synaptic input and results from the dynamic changes in the expression of Na+/K+/2Cl? co-transporter NKCC1 driving Cl? influx and neuron-specific K+/Cl? co-transporter KCC2 driving Cl? efflux. The developmental transition of KCC2 expression is regulated by Disrupted-in-Schizophrenia 1 (DISC1) and brain-derived neurotrophic factor (BDNF) signaling. The excitatory GABA signaling during early neurogenesis is important to the activity/experience-induced regulation of NSC quiescence, NPC proliferation, neuroblast migration and newborn neuronal maturation/functional integration. The inhibitory GABA signaling allows for the sparse and static functional networking essential for learning/memory development and maintenance. PMID:24285940

PONTES, Adalto; ZHANG, Yonggang; HU, Wenhui



Stimulation of GABA release by scorpion venom in an isolated synapse in the crayfish (Astacus leptodactylus).  


Effects of various types of scorpion venom on gamma-aminobutyric acid (GABA) release were studied in an isolated synapse in the crayfish. Post-synaptic GABA-induced currents were recorded to monitor the GABA release from the pre-synaptic site. In 20mM tetraethylammonium (TEA) chloride solution the GABA-induced currents increased 71%. Exposing the preparations to Leiurus quinquestriatus hebraeus, Leiurus quinquestriatus quinquestriatus or Tityus serrulatus venom (0.1mg/ml) increased GABA-induced currents 4-5 fold. The effect was present in the presence of tetrodotoxin (TTX) but diminished significantly when verapamil was applied. Exposing the preparations Androctonus australis or Buthus tamulus venom did not affect the GABA-induced currents. The results indicate that stimulation of the GABA release by some of the scorpion venoms may partly be due to a possible block of pre-synaptic potassium channels, but not due to an abnormal increase in sodium channel activation. PMID:12565762

Purali, Nuhan



Nonsynaptic GABA signaling in postnatal subventricular zone controls proliferation of GFAP-expressing progenitors.  


In the postnatal subventricular zone (SVZ), local cues or signaling molecules released from neuroblasts limit the proliferation of glial fibrillary acidic protein (GFAP)-expressing progenitors thought to be stem cells. However, signals between SVZ cells have not been identified. We show that depolarization of neuroblasts induces nonsynaptic SNARE-independent GABA(A) receptor currents in GFAP-expressing cells, the time course of which depends on GABA uptake in acute mouse slices. We found that GABA(A) receptors are tonically activated in GFAP-expressing cells, consistent with the presence of spontaneous depolarizations in neuroblasts that are sufficient to induce GABA release. These data demonstrate the existence of nonsynaptic GABAergic signaling between neuroblasts and GFAP-expressing cells. Furthermore, we show that GABA(A) receptor activation in GFAP-expressing cells limits their progression through the cell cycle. Thus, as GFAP-expressing cells generate neuroblasts, GABA released from neuroblasts provides a feedback mechanism to control the proliferation of GFAP-expressing progenitors by activating GABA(A) receptors. PMID:16116450

Liu, Xiuxin; Wang, Qin; Haydar, Tarik F; Bordey, Angélique



Comparison of taurine, GABA, Glu, and Asp as scavengers of malondialdehyde in vitro and in vivo  

PubMed Central

The purpose of this study is to determine if amino acid neurotransmitters such as gamma-aminobutyric acid (GABA), taurine, glutamate (Glu), and aspartate (Asp) can scavenge activated carbonyl toxicants. In vitro, direct reaction between malondialdehyde (MDA) and amino acids was researched using different analytical methods. The results indicated that scavenging activated carbonyl function of taurine and GABA is very strong and that of Glu and Asp is very weak in pathophysiological situations. The results provided perspective into the reaction mechanism of taurine and GABA as targets of activated carbonyl such as MDA in protecting nerve terminals. In vivo, we studied the effect of taurine and GABA as antioxidants by detecting MDA concentration and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. It was shown that MDA concentration was decreased significantly, and the activities of SOD and GSH-Px were increased significantly in the cerebral cortex and hippocampus of acute epileptic state rats, after the administration of taurine and GABA. The results indicated that the peripherally administered taurine and GABA can scavenge free radicals and protect the tissue against activated carbonyl in vivo and in vitro. PMID:23618076



Genetic heterogeneity for autosomal recessive pyridoxine-dependent seizures  

Microsoft Academic Search

Pyridoxine-dependent seizure (PDS) is a rare autosomal recessive intractable seizure disorder only controlled by a daily supplementation\\u000a of pharmacological doses of pyridoxine (Vitamin B6). Although glutamate decarboxylase utilizes pyridoxal phosphate as a cofactor\\u000a during conversion of the excitatory amino acid, glutamate, to the inhibitory neurotransmitter, ?-amino butyric acid (GABA),\\u000a several studies have failed to demonstrate a linkage to either of

C. L. Bennett; H. M. Huynh; P. F. Chance; I. A. Glass; S. M. Gospe



An Update on GABA? Receptors  

PubMed Central

The present review discusses the functional and molecular diversity of GABA? receptors. These receptors were originally described in the mammalian retina, and their functional role in the visual pathway has been recently elucidated; however new studies on their distribution in the brain and spinal cord have revealed that they are more spread than originally thought, and thus it will be important to determine their physiological contribution to the GABAergic transmission in other areas of the central nervous system. In addition, molecular modeling has revealed peculiar traits of these receptors that have impacted on the interpretations of the latest pharmacolgical and biophysical findings. Finally, sequencing of several vertebrate genomes has permitted a comparative analysis of the organization of the GABA? genes. PMID:21629448

Martinez-Delgado, Gustavo; Estrada-Mondragon, Argel; Miledi, Ricardo; Martinez-Torres, Ataulfo



GABA Pharmacology: The Search for Analgesics.  


Decades of research have been devoted to defining the role of GABAergic transmission in nociceptive processing. Much of this work was performed using rigid, orthosteric GABA analogs created by Povl Krogsgaard-Larsen and his associates. A relationship between GABA and pain is suggested by the anatomical distribution of GABA receptors and the ability of some GABA agonists to alter nociceptive responsiveness. Outlined in this report are data supporting this proposition, with particular emphasis on the anatomical localization and function of GABA-containing neurons and the molecular and pharmacological properties of GABAA and GABAB receptor subtypes. Reference is made to changes in overall GABAergic tone, GABA receptor expression and activity as a function of the duration and intensity of a painful stimulus or exposure to GABAergic agents. Evidence is presented that the plasticity of this receptor system may be responsible for the variability in the antinociceptive effectiveness of compounds that influence GABA transmission. These findings demonstrate that at least some types of persistent pain are associated with a regionally selective decline in GABAergic tone, highlighting the need for agents that enhance GABA activity in the affected regions without compromising GABA function over the long-term. As subtype selective positive allosteric modulators may accomplish these goals, such compounds might represent a new class of analgesic drugs. PMID:24532294

McCarson, Kenneth E; Enna, S J



Presynaptic mGlu7 receptors control GABA release in mouse hippocampus.  


The functional role of presynaptic release-regulating metabotropic glutamate type 7 (mGlu7) receptors in hippocampal GABAergic terminals was investigated. Mouse hippocampal synaptosomes were preloaded with [(3)H]D-?-aminobutyric acid ([(3)H]GABA) and then exposed in superfusion to 12 mM KCl. The K(+)-evoked [(3)H]GABA release was inhibited by the mGlu7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082, 0.001-10 ?M), as well as by the group III mGlu receptor agonist l-(+)-2-amino-4-phosphonobutyric acid [(l)-AP4, 0.01-1 mM]. The mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG, 10-100 nM] was ineffective. AMN082 and (l)-AP4-induced effects were recovered by the mGlu7 negative allosteric modulator (NAM) 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP). AMN082 also inhibited in a MMPIP-sensitive manner the K(+)-evoked release of endogenous GABA. AMN082 and the adenylyl cyclase (AC) inhibitor MDL-12,330A reduced [(3)H]GABA exocytosis in a 8-Br-cAMP-sensitive. AMN082-inhibitory effect was additive to that caused by (-)baclofen, but insensitive to the GABA(B) antagonist 3-[[(3,4-Dichlorophenyl)methyl]amino]propyl] diethoxymethyl) phosphinic acid (CGP52432). Conversely, (-)baclofen-induced inhibition of GABA exocytosis was insensitive to MMPIP. Finally, the forskolin-evoked [(3)H]GABA release was reduced by AMN082 or (-)baclofen but abolished when the two agonists were added concomitantly. Mouse hippocampal synaptosomal plasmamembranes posses mGlu7 receptor proteins; confocal microscopy analysis unveiled that mGlu7 proteins colocalize with syntaxin-1A (Stx-1A), with vesicular GABA transporter (VGAT)-proteins and with GABA(B) receptor subunit proteins. We propose that presynaptic inhibitory mGlu7 heteroreceptors, negatively coupled to AC-dependent intraterminal pathway, exist in mouse hippocampal GABA-containing terminals, where they colocalize, but do not functionally cross-talk, with GABA(B) autoreceptors. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID:22564442

Summa, Maria; Di Prisco, Silvia; Grilli, Massimo; Usai, Cesare; Marchi, Mario; Pittaluga, Anna



Synthesis of novel cognition enhancers with pyrazolo[5,1-c][1,2,4]benzotriazine core acting at ?-aminobutyric acid type A (GABA(A)) receptor.  


Memory dysfunction associated with aging, neurodegenerative and psychiatric disorders represents an increasing medical need. Advances in research exploring the biological mechanisms underlying learning and memory have opened new potential approaches for development of memory-enhancing therapies addressed to selective neuronal targets. In this work, we synthesized some derivatives with a pyrazolo[5,1-c][1,2,4]benzotriazine core to identify ligands on GABAA receptors subtype (benzodiazepine site on GABAA-receptor) endowed with the potential of enhancing cognition activity without the side effects usually associated with non-selective GABAA modulators. In fact, there is much evidence that GABAA-R (?-aminobutyric acid, type A receptor) subtype ligands have relevance in learning and memory. In vitro and in vivo tests have been performed. Pharmacological data indicate that compounds 7, 13, 14 and 22 act as dual functional modulators of GABAA-Rs (promnemonic and anxiolytic agents) while only compounds 3 and 10 stand out as selectively displaying good antiamnesic and procognitive activity (1 and 3 mg/kg, respectively). PMID:23490154

Guerrini, Gabriella; Ciciani, Giovanna; Costanzo, Annarella; Daniele, Simona; Martini, Claudia; Ghelardini, Carla; Di Cesare Mannelli, Lorenzo; Ciattini, Samuele



mRNA and Protein Levels for GABA[subscript A][alpha]4, [alpha]5, [beta]1 and GABA[subscript B]R1 Receptors are Altered in Brains from Subjects with Autism  

ERIC Educational Resources Information Center

We have shown altered expression of gamma-aminobutyric acid A (GABA[subscript A]) and gamma-aminobutyric acid B (GABA[subscript B]) receptors in the brains of subjects with autism. In the current study, we sought to verify our western blotting data for GABBR1 via qRT-PCR and to expand our previous work to measure mRNA and protein levels of 3…

Fatemi, S. Hossein; Reutiman, Teri J.; Folsom, Timothy D.; Rooney, Robert J.; Patel, Diven H.; Thuras, Paul D.



A Simple Method for Determining the Absolute Configuration of a-Amino Acids  

NASA Astrophysics Data System (ADS)

The reaction of [Pd(dmba)(acac)] (dmba = C6H4CH2NMe2-2 or 2-[(dimethylamino)methyl]phenyl-C1,N; acac = C5H7O2 or acetylacetonate) with optically pure a-amino acids (HAa, 1:1 molar ratio) [HAa = S-alanine, S-2-amino butyric acid, R-2-amino butyric acid, (2S,3S)-isoleucine, (2S,3R)-threonine and S-asparagine] in refluxing MeOH results in the formation of the corresponding neutral complexes [Pd(dmba)(Aa)] in good yield. The CD (circular dichroism) spectra of these complexes have been measured. The analysis of the shape of the CD curves reveals that all complexes with the same configuration at Ca display similar CD curves, whereas complexes with opposite configuration at Ca display CD curves that are mirror images. Thus, these complexes could be used as analytical tools in the assignment of absolute configurations of a-amino acids.

Díaz-de-Villegas, María Dolores; Urriolabeitia, Esteban P.



Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone.  


Chronic obstructive pulmonary disease and asthma are characterized by hyperreactive airway responses that predispose patients to episodes of acute airway constriction. Recent studies suggest a complex paradigm of GABAergic signaling in airways that involves GABA-mediated relaxation of airway smooth muscle. However, the cellular source of airway GABA and mechanisms regulating its release remain unknown. We questioned whether epithelium is a major source of GABA in the airway and whether the absence of epithelium-derived GABA contributes to greater airway smooth muscle force. Messenger RNA encoding glutamic acid decarboxylase (GAD) 65/67 was quantitatively measured in human airway epithelium and smooth muscle. HPLC quantified GABA levels in guinea pig tracheal ring segments under basal or stimulated conditions with or without epithelium. The role of endogenous GABA in the maintenance of an acetylcholine contraction in human airway and guinea pig airway smooth muscle was assessed in organ baths. A 37.5-fold greater amount of mRNA encoding GAD 67 was detected in human epithelium vs. airway smooth muscle cells. HPLC confirmed that guinea pig airways with intact epithelium have a higher constitutive elution of GABA under basal or KCl-depolarized conditions compared with epithelium-denuded airway rings. Inhibition of GABA transporters significantly suppressed KCl-mediated release of GABA from epithelium-intact airways, but tetrodotoxin was without effect. The presence of intact epithelium had a significant GABAergic-mediated prorelaxant effect on the maintenance of contractile tone. Airway epithelium is a predominant cellular source of endogenous GABA in the airway and contributes significant prorelaxant GABA effects on airway smooth muscle force. PMID:23204068

Gallos, George; Townsend, Elizabeth; Yim, Peter; Virag, Laszlo; Zhang, Yi; Xu, Dingbang; Bacchetta, Matthew; Emala, Charles W



Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone  

PubMed Central

Chronic obstructive pulmonary disease and asthma are characterized by hyperreactive airway responses that predispose patients to episodes of acute airway constriction. Recent studies suggest a complex paradigm of GABAergic signaling in airways that involves GABA-mediated relaxation of airway smooth muscle. However, the cellular source of airway GABA and mechanisms regulating its release remain unknown. We questioned whether epithelium is a major source of GABA in the airway and whether the absence of epithelium-derived GABA contributes to greater airway smooth muscle force. Messenger RNA encoding glutamic acid decarboxylase (GAD) 65/67 was quantitatively measured in human airway epithelium and smooth muscle. HPLC quantified GABA levels in guinea pig tracheal ring segments under basal or stimulated conditions with or without epithelium. The role of endogenous GABA in the maintenance of an acetylcholine contraction in human airway and guinea pig airway smooth muscle was assessed in organ baths. A 37.5-fold greater amount of mRNA encoding GAD 67 was detected in human epithelium vs. airway smooth muscle cells. HPLC confirmed that guinea pig airways with intact epithelium have a higher constitutive elution of GABA under basal or KCl-depolarized conditions compared with epithelium-denuded airway rings. Inhibition of GABA transporters significantly suppressed KCl-mediated release of GABA from epithelium-intact airways, but tetrodotoxin was without effect. The presence of intact epithelium had a significant GABAergic-mediated prorelaxant effect on the maintenance of contractile tone. Airway epithelium is a predominant cellular source of endogenous GABA in the airway and contributes significant prorelaxant GABA effects on airway smooth muscle force. PMID:23204068

Townsend, Elizabeth; Yim, Peter; Virag, Laszlo; Zhang, Yi; Xu, Dingbang; Bacchetta, Matthew; Emala, Charles W.



Benzodiazepine treatment induces subtype-specific changes in GABA(A) receptor trafficking and decreases synaptic inhibition.  


Benzodiazepines potentiate ?-aminobutyric acid type A receptor (GABA(A)R) activity and are widely prescribed to treat anxiety, insomnia, and seizure disorders. Unfortunately, clinical use of benzodiazepines (BZs) is severely limited by tolerance. The mechanisms leading to BZ tolerance are unknown. BZs bind at the interface between an ? and ? subunit of GABA(A)Rs, preferentially enhancing synaptic receptors largely composed of ?(1-3, 5), ?3, and ?2 subunits. Using confocal imaging and patch-clamp approaches, we show that treatment with the BZ flurazepam decreases GABA(A)R surface levels and the efficacy of neuronal inhibition in hippocampal neurons. A dramatic decrease in surface and total levels of ?2 subunit-containing GABA(A)Rs occurred within 24 h of flurazepam treatment, whereas GABA(A)Rs incorporating ?1 subunits showed little alteration. The GABA(A)R surface depletion could be reversed by treatment with the BZ antagonist Ro 15-1788. Coincident with decreased GABA(A)R surface levels, flurazepam treatment reduced miniature inhibitory postsynaptic current amplitude, which returned to control levels with acute Ro 15-1788 treatment. GABA(A)R endocytosis and insertion rates were unchanged by flurazepam treatment. Treatment with leupeptin restored flurazepam lowered receptor surface levels, strongly suggesting that flurazepam increases lysosomal degradation of GABA(A)Rs. Together, these data suggest that flurazepam exposure enhances degradation of ?2 subunit-containing GABA(A)Rs after their removal from the plasma membrane, leading to a reduction in inhibitory synapse size and number along with a decrease in the efficacy of synaptic inhibition. These reported subtype-specific changes in GABA(A)R trafficking provide significant mechanistic insight into the initial neuroadaptive responses occurring with BZ treatment. PMID:23091016

Jacob, Tija C; Michels, Guido; Silayeva, Liliya; Haydon, Julia; Succol, Francesca; Moss, Stephen J



Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment.  


The lateral habenula (LHb), a key regulator of monoaminergic brain regions, is activated by negatively valenced events. Its hyperactivity is associated with depression. Although enhanced excitatory input to the LHb has been linked to depression, little is known about inhibitory transmission. We discovered that ?-aminobutyric acid (GABA) is co-released with its functional opponent, glutamate, from long-range basal ganglia inputs (which signal negative events) to limit LHb activity in rodents. At this synapse, the balance of GABA/glutamate signaling is shifted toward reduced GABA in a model of depression and increased GABA by antidepressant treatment. GABA and glutamate co-release therefore controls LHb activity, and regulation of this form of transmission may be important for determining the effect of negative life events on mood and behavior. PMID:25237099

Shabel, Steven J; Proulx, Christophe D; Piriz, Joaquin; Malinow, Roberto



GABA localization in the nematode Ascaris  

SciTech Connect

A histochemical approach was used to examine the distribution of GABA-associated neurons in the nematode Ascaris, an organism whose small number of morphologically simple neurons make it an excellent preparation for analyzing neuronal phenotypes. Two GABAergic markers were examined: GABA-like immunoreactivity (GLIR), a marker for endogenous stores of GABA; and ({sup 3}H)-GABA uptake, a marker for GABA uptake sites. Strong GLIR was present in the cell bodies, neurites and commissures of dorsal and ventral inhibitory motorneurons present in this region. Strong GLIR was also present in the cell bodies and processes of the four RME neurons in the nerve ring and in several other ganglionic neurons. Staining was absent in excitatory motorneurons, in ventral cord interneurons and in muscle cells and hypodermis. GABA uptake sites were found in single neural processes in both the ventral and dorsal nerve cords. ({sup 3}H)-GABA labeling was also observed in the other two RME cells and several other cephalic neurons. Four putative cholinergic excitatory motorneurons in the retrovesicular ganglion (RVG) were heavily labeled. Ventral and dorsal nerve cord inhibitory motorneurons did not take up ({sup 3}H)-GABA. Labeling of the ventral cord excitatory motorneuron somata and cell bodies was at or slightly above background. Heavy labeling of muscle cells was also observed.

Guastella, J.



Genome Sequence of Lactococcus lactis subsp. lactis NCDO 2118, a GABA-Producing Strain  

PubMed Central

Lactococcus lactis subsp. lactis NCDO 2118 is a nondairy lactic acid bacterium, a xylose fermenter, and a gamma-aminobutyric acid (GABA) producer isolated from frozen peas. Here, we report the complete genome sequence of L. lactis NCDO 2118, a strain with probiotic potential activity. PMID:25278529

Oliveira, Leticia C.; Saraiva, Tessalia D. L.; Soares, Siomar C.; Ramos, Rommel T. J.; Sa, Pablo H. C. G.; Carneiro, Adriana R.; Miranda, Fabio; Freire, Matheus; Renan, Wendel; Junior, Alberto F. O.; Santos, Anderson R.; Pinto, Anne C.; Souza, Bianca M.; Castro, Camila P.; Diniz, Carlos A. A.; Rocha, Clarissa S.; Mariano, Diego C. B.; de Aguiar, Edgar L.; Folador, Edson L.; Barbosa, Eudes G. V.; Aburjaile, Flavia F.; Goncalves, Lucas A.; Guimaraes, Luis C.; Azevedo, Marcela; Agresti, Pamela C. M.; Silva, Renata F.; Tiwari, Sandeep; Almeida, Sintia S.; Hassan, Syed S.; Pereira, Vanessa B.; Abreu, Vinicius A. C.; Pereira, Ulisses P.; Dorella, Fernanda A.; Carvalho, Alex F.; Pereira, Felipe L.; Leal, Carlos A. G.; Figueiredo, Henrique C. P.; Silva, Artur; Miyoshi, Anderson



Prefrontal cortical GABA transmission modulates discrimination and latent inhibition of conditioned fear: relevance for schizophrenia.  


Inhibitory gamma-aminobutyric acid (GABA) transmission within the prefrontal cortex (PFC) regulates numerous functions, and perturbations in GABAergic transmission within this region have been proposed to contribute to some of the cognitive and behavioral abnormalities associated with disorders such as schizophrenia. These abnormalities include deficits in emotional regulation and aberrant attributions of affective salience. Yet, how PFC GABA regulates these types of emotional processes are unclear. To address this issue, we investigated the contribution of PFC GABA transmission to different aspects of Pavlovian emotional learning in rats using translational discriminative fear conditioning and latent inhibition (LI) assays. Reducing prelimbic PFC GABAA transmission via infusions of the antagonist bicuculline before the acquisition or expression of fear conditioning eliminated the ability to discriminate between an aversive conditioned stimulus (CS+) paired with footshock vs a neutral CS-, resembling similar deficits observed in schizophrenic patients. In a separate experiment, blockade of PFC GABAA receptors before CS preexposure (PE) and conditioning did not affect subsequent expression of LI, but did enhance fear in rats that were not preexposed to the CS. In contrast, PFC GABA-blockade before a fear expression test disrupted the recall of learned irrelevance and abolished LI. These data suggest that normal PFC GABA transmission is critical for regulating and mitigating multiple aspects of aversive learning, including discrimination between fear vs safety signals and recall of information about the irrelevance of stimuli. Furthermore, they suggest that similar deficits in emotional regulation observed in schizophrenia may be driven in part by deficient PFC GABA activity. PMID:24784549

Piantadosi, Patrick T; Floresco, Stan B



GABA Expression and Regulation by Sensory Experience in the Developing Visual System  

PubMed Central

The developing retinotectal system of the Xenopus laevis tadpole is a model of choice for studying visual experience-dependent circuit maturation in the intact animal. The neurotransmitter gamma-aminobutyric acid (GABA) has been shown to play a critical role in the formation of sensory circuits in this preparation, however a comprehensive neuroanatomical study of GABAergic cell distribution in the developing tadpole has not been conducted. We report a detailed description of the spatial expression of GABA immunoreactivity in the Xenopus laevis tadpole brain at two key developmental stages: stage 40/42 around the onset of retinotectal innervation and stage 47 when the retinotectal circuit supports visually-guided behavior. During this period, GABAergic neurons within specific brain structures appeared to redistribute from clusters of neuronal somata to a sparser, more uniform distribution. Furthermore, we found that GABA levels were regulated by recent sensory experience. Both ELISA measurements of GABA concentration and quantitative analysis of GABA immunoreactivity in tissue sections from the optic tectum show that GABA increased in response to a 4 hr period of enhanced visual stimulation in stage 47 tadpoles. These observations reveal a remarkable degree of adaptability of GABAergic neurons in the developing brain, consistent with their key contributions to circuit development and function. PMID:22242157

Miraucourt, Lois S.; da Silva, Jorge Santos; Burgos, Kasandra; Li, Jianli; Abe, Hikari; Ruthazer, Edward S.; Cline, Hollis T.



Defects in GABA metabolism affect selective autophagy pathways and are alleviated by mTOR inhibition.  


In addition to key roles in embryonic neurogenesis and myelinogenesis, ?-aminobutyric acid (GABA) serves as the primary inhibitory mammalian neurotransmitter. In yeast, we have identified a new role for GABA that augments activity of the pivotal kinase, Tor1. GABA inhibits the selective autophagy pathways, mitophagy and pexophagy, through Sch9, the homolog of the mammalian kinase, S6K1, leading to oxidative stress, all of which can be mitigated by the Tor1 inhibitor, rapamycin. To confirm these processes in mammals, we examined the succinic semialdehyde dehydrogenase (SSADH)-deficient mouse model that accumulates supraphysiological GABA in the central nervous system and other tissues. Mutant mice displayed increased mitochondrial numbers in the brain and liver, expected with a defect in mitophagy, and morphologically abnormal mitochondria. Administration of rapamycin to these mice reduced mTOR activity, reduced the elevated mitochondrial numbers, and normalized aberrant antioxidant levels. These results confirm a novel role for GABA in cell signaling and highlight potential pathomechanisms and treatments in various human pathologies, including SSADH deficiency, as well as other diseases characterized by elevated levels of GABA. PMID:24578415

Lakhani, Ronak; Vogel, Kara R; Till, Andreas; Liu, Jingjing; Burnett, Sarah F; Gibson, K Michael; Subramani, Suresh



Novel dose-dependent alterations in excitatory GABA during embryonic development associated with lead (Pb) neurotoxicity.  


Lead (Pb) is a heavy metal that is toxic to numerous physiological processes. Its use in industrial applications is widespread and results in an increased risk of human environmental exposure. The central nervous system (CNS) is most sensitive to Pb exposure during early development due to rapid cell proliferation and migration, axonal growth, and synaptogenesis. One of the key components of CNS development is the Gamma-aminobutyric acid (GABA)-ergic system. GABA is the primary inhibitory neurotransmitter in the adult brain. However, during development GABA acts as an excitatory neurotrophic factor which contributes to these cellular processes. Multiple studies report effects of Pb on GABA in the mature brain; however, little is known regarding the adverse effects of Pb exposure on the GABAergic system during embryonic development. To characterize the effects of Pb on the GABAergic system during development, zebrafish embryos were exposed to 10, 50, or 100 ppb Pb or a control treatment. Tissue up-take, gross morphological alterations, gene expression, and neurotransmitter levels were analyzed. Analysis revealed that alterations in gene expression throughout the GABAergic system and GABA levels were dose and developmental time point specific. These data provide a framework for further analysis of the effects of Pb on the GABAergic system during the excitatory phase and as GABA transitions to an inhibitory neurotransmitter during development. PMID:24875535

Wirbisky, Sara E; Weber, Gregory J; Lee, Jang-Won; Cannon, Jason R; Freeman, Jennifer L



Thalamic GABA Predicts Fine Motor Performance in Manganese-Exposed Smelter Workers  

PubMed Central

Overexposure to manganese (Mn) may lead to parkinsonian symptoms including motor deficits. The main inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is known to play a pivotal role in the regulation and performance of movement. Therefore this study was aimed at testing the hypothesis that an alteration of GABA following Mn exposure may be associated with fine motor performance in occupationally exposed workers and may underlie the mechanism of Mn-induced motor deficits. A cohort of nine Mn-exposed male smelter workers from an Mn-iron alloy factory and 23 gender- and age-matched controls were recruited and underwent neurological exams, magnetic resonance spectroscopy (MRS) measurements, and Purdue pegboard motor testing. Short-echo-time MRS was used to measure N-Acetyl-aspartate (NAA) and myo-inositol (mI). GABA was detected with a MEGA-PRESS J-editing MRS sequence. The mean thalamic GABA level was significantly increased in smelter workers compared to controls (p?=?0.009). Multiple linear regression analysis reveals (1) a significant association between the increase in GABA level and the duration of exposure (R2?=?0.660, p?=?0.039), and (2) significant inverse associations between GABA levels and all Purdue pegboard test scores (for summation of all scores R2?=?0.902, p?=?0.001) in the smelter workers. In addition, levels of mI were reduced significantly in the thalamus and PCC of smelter workers compared to controls (p?=?0.030 and p?=?0.009, respectively). In conclusion, our results show clear associations between thalamic GABA levels and fine motor performance. Thus in Mn-exposed subjects, increased thalamic GABA levels may serve as a biomarker for subtle deficits in motor control and may become valuable for early diagnosis of Mn poisoning. PMID:24505436

Long, Zaiyang; Li, Xiang-Rong; Xu, Jun; Edden, Richard A. E.; Qin, Wei-Ping; Long, Li-Ling; Murdoch, James B.; Zheng, Wei; Jiang, Yue-Ming; Dydak, Ulrike



Thalamic GABA predicts fine motor performance in manganese-exposed smelter workers.  


Overexposure to manganese (Mn) may lead to parkinsonian symptoms including motor deficits. The main inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is known to play a pivotal role in the regulation and performance of movement. Therefore this study was aimed at testing the hypothesis that an alteration of GABA following Mn exposure may be associated with fine motor performance in occupationally exposed workers and may underlie the mechanism of Mn-induced motor deficits. A cohort of nine Mn-exposed male smelter workers from an Mn-iron alloy factory and 23 gender- and age-matched controls were recruited and underwent neurological exams, magnetic resonance spectroscopy (MRS) measurements, and Purdue pegboard motor testing. Short-echo-time MRS was used to measure N-Acetyl-aspartate (NAA) and myo-inositol (mI). GABA was detected with a MEGA-PRESS J-editing MRS sequence. The mean thalamic GABA level was significantly increased in smelter workers compared to controls (p = 0.009). Multiple linear regression analysis reveals (1) a significant association between the increase in GABA level and the duration of exposure (R(2)?= 0.660, p = 0.039), and (2) significant inverse associations between GABA levels and all Purdue pegboard test scores (for summation of all scores R(2)?= 0.902, p = 0.001) in the smelter workers. In addition, levels of mI were reduced significantly in the thalamus and PCC of smelter workers compared to controls (p = 0.030 and p = 0.009, respectively). In conclusion, our results show clear associations between thalamic GABA levels and fine motor performance. Thus in Mn-exposed subjects, increased thalamic GABA levels may serve as a biomarker for subtle deficits in motor control and may become valuable for early diagnosis of Mn poisoning. PMID:24505436

Long, Zaiyang; Li, Xiang-Rong; Xu, Jun; Edden, Richard A E; Qin, Wei-Ping; Long, Li-Ling; Murdoch, James B; Zheng, Wei; Jiang, Yue-Ming; Dydak, Ulrike



Role of GABA in electro-acupuncture therapy on cerebral ischemia induced by occlusion of the middle cerebral artery in rats  

Microsoft Academic Search

This study investigated the possible involvement of ?-aminobutyric acid (GABA) in the therapeutic effect of cerebral ischemia by electro-acupuncture (EA) using the rat model with middle cerebral artery occlusion (MCAO). By immunohistochemistry, the changes of GABA expression level in the primary infarct area and its penumbral regions were examined. The changes in infarct area and survival neuron percentages were also

Ping Gan; Jie-Shi Cheng; Yee-Kong Ng; Eng-Ang Ling



GABA A,slow: causes and consequences.  


GABA(A) receptors in the CNS mediate both fast synaptic and tonic inhibition. Over the past decade a phasic current with features intermediate between fast synaptic and tonic inhibition, termed GABA(A,slow), has received increasing attention. This has coincided with an ever-growing appreciation for GABAergic cell type diversity. Compared with classical fast synaptic inhibition, GABA(A,slow) is slower by an order of magnitude. In this review, we summarize recent studies that have enhanced our understanding of GABA(A,slow). These include the discovery of specialized interneuron types from which this current originates, the factors that could underlie its characteristically slow kinetics, its contribution to specific aspects of integrative function and network oscillations, and its potential usefulness as a novel drug target for modulating inhibitory synaptic transmission in the CNS. PMID:21145601

Capogna, Marco; Pearce, Robert A



GABA Expression and Regulation by Sensory Experience in the Developing Visual System  

Microsoft Academic Search

The developing retinotectal system of the Xenopus laevis tadpole is a model of choice for studying visual experience-dependent circuit maturation in the intact animal. The neurotransmitter gamma-aminobutyric acid (GABA) has been shown to play a critical role in the formation of sensory circuits in this preparation, however a comprehensive neuroanatomical study of GABAergic cell distribution in the developing tadpole has

Loïs S. Miraucourt; Jorge Santos da Silva; Kasandra Burgos; Jianli Li; Hikari Abe; Edward S. Ruthazer; Hollis T. Cline



Reversal or reduction of glutamate and GABA transport in CNS pathology and therapy  

Microsoft Academic Search

A dysfunction of amino acid neurotransmitter transporters occurs in a number of central nervous system disorders, including stroke, epilepsy, cerebral palsy and amyotrophic lateral sclerosis. This dysfunction can comprise a reversal of transport direction, leading to the release of neurotransmitter into the extracellular space, or an alteration in transporter expression level. This review analyses the role of glutamate and GABA

Nicola J. Allen; Ragnhildur Káradóttir; David Attwell



Specific subtypes of cortical GABA interneurons contribute to the neurovascular coupling response to basal forebrain stimulation  

Microsoft Academic Search

Neurovascular coupling, or the tight coupling between neuronal activity and regional cerebral blood flow (CBF), seems largely driven by the local processing of incoming afferent signals within the activated area. To test if cortical ?-aminobutyric acid (GABA) interneurons—the local integrators of cortical activity—are involved in this coupling, we stimulated the basalocortical pathway in vivo, monitored cortical CBF, and identified the

Ara Kocharyan; Priscilla Fernandes; Xin-Kang Tong; Elvire Vaucher; Edith Hamel



The effects of pentobarbital and benzodiazepines on GABA-responses in the periphery and spinal cord in vitro.  


Pentobarbital and benzodiazepines were compared in their interaction with the gamma-aminobutyric acid (GABA) antagonists picrotoxin and bicuculline on GABAA receptor-mediated events. On excised vagal nerves and dorsal roots pentobarbital, in contrast to the benzodiazepines diazepam, lorazepam and flurazepam, was able to enhance GABA-induced depolarizations recorded in the presence of picrotoxin or bicuculline. On hemicord preparations picrotoxin simultaneously depressed the electrically evoked dorsal root-dorsal root potential and enhanced the dorsal root-ventral root potential. Pentobarbital overcame the effects of picrotoxin, whereas diazepam and midazolam were without effect. These results may be explained by the suggestion that the GABA receptors in these test systems are not tightly associated with the benzodiazepine receptor activated by diazepam, lorazepam, midazolam and flurazepam, and correspond to the recently described GABAA2 subdivision of GABA receptors. PMID:1658694

Wesselman, J P; van Wilgenburg, H; Long, S K



The effects of local perfusion of DAMGO on extracellular GABA and glutamate concentrations in the rostral ventromedial medulla.  


Electrophysiological data suggest an involvement of rostral ventromedial medulla (RVM) GABA and glutamate (GLU) neurons in morphine analgesia. Direct evidence that extracellular concentrations of GABA or GLU are altered in response to mu opioid receptor (MOP-R) activation is, however, lacking. We used in vivo microdialysis to investigate this issue. Basal GABA overflow increased in response to intra-RVM perfusion of KCl (60 mmol/L). Reverse microdialysis of the MOP-R agonist D-Ala(2),NMePhe(4),Gly-ol(5)]enkephalin (DAMGO) (20-500 micromol/L) produced a concentration-dependent decrease of RVM GABA overflow. Behavioral testing revealed that concentrations that decreased GABA levels increased thermal withdrawal thresholds. A lower agonist concentration that did not increase GABA failed to alter thermal thresholds. DAMGO did not alter GLU concentrations. However, KCl also failed to modify GLU release. Since rapid, transporter-mediated uptake may mask the detection of changes in GLU release, the selective excitatory amino acid transporter inhibitor pyrrolidine-2,4-dicarboxylic acid (tPDC, 0.6 mmol/L) was added to the perfusion medium for subsequent studies. tPDC increased GLU concentrations, confirming transport inhibition. KCl increased GLU dialysate levels in the presence of tPDC, demonstrating that transport inhibition permits detection of depolarization-evoked GLU overflow. In the presence of tPDC, DAMGO increased GLU overflow in a concentration-dependent manner. These data demonstrate that MOP-R activation decreases GABA and increases GLU release in the RVM. We hypothesize that the opposing effects of MOP-R on GLU and GABA transmission contribute to opiate antinociception. PMID:17961151

Schepers, Raf Jan-Filip; Mahoney, Janet Lynn; Zapata, Agustin; Chefer, Vladimir; Shippenberg, Toni Shaun



Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones.  


1. The effects of benzodiazepines and non-benzodiazepine compounds on the gamma-aminobutyric acid (GABA)-induced chloride current (ICl) were studied in frog isolated sensory neurones by use of a concentration-jump (termed 'concentration-clamp') technique, under single-electrode voltage-clamp conditions. The drugs used were classified into four categories as follows: full benzodiazepine receptor agonists (diazepam, clonazepam, nitrazepam, midazolam, clotiazepam and etizolam), partial agonists (CL 218,872, Ro 16-6028, Ro 17-1812 and Ro 23-0364), inverse agonists (Ro 15-3505, FG 7142 and beta-CCE) and a benzodiazepine receptor antagonist, Ro 15-1788 (flumazenil). 2. All full agonists at concentrations of 3 x 10(-6) M or less increased dose-dependently the peak amplitude of ICl elicited by 3 x 10(-6) M GABA to twice to three times larger than the control. However, no further augmentation of the GABA response was observed at concentrations of 1 x 10(-5) M or higher. Partial agonists also showed a dose-dependent augmentation of the GABA response at concentrations ranging from 3 x 10(-8) M to 3 x 10(-5) M, but their efficacies of augmentation of the GABA response were only about half or less of those of full agonists. Of the inverse agonists, beta-CCE had a unique dose-dependent effect on the GABA response. Beta-CCE reduced dose-dependently the GABA response at concentrations of less than 3 x 10(-6) M, but augmented it at concentrations of 3 x 10(-5) M and 6 x 10(-5) M. The inverse agonists reduced dose-dependently the GABA response. The benzodiazepine antagonist, flumazenil, slightly augmented the GABA response at concentrations between 3 x 10 7M and 3 x 10 5 M. 3. These results show clear differences in the effects on the GABA response between these four categories of compounds known to affect the benzodiazepine recognition site of the GABA/ benzodiazepine receptor-chloride channel complex. Our experimental system of frog isolated sensory neurones and a 'concentration-clamp' technique appears to be useful for evaluating efficacy of compounds on responses mediated by the GABA/benzodiazepine receptor-chloride channel complex. PMID:2574062

Yakushiji, T; Fukuda, T; Oyama, Y; Akaike, N



GABAÃÂs Control of Stem and Cancer Cell Proliferation in Adult Neural and Peripheral Niches  

NSDL National Science Digital Library

Aside from traditional neurotransmission and regulation of secretion, {gamma}-amino butyric acid (GABA) through GABAA receptors negatively regulates proliferation of pluripotent and neural stem cells in embryonic and adult tissue. There has also been evidence that GABAergic signaling and its control over proliferation is not only limited to the nervous system, but is widespread through peripheral organs containing adult stem cells. GABA has emerged as a tumor signaling molecule in the periphery that controls the proliferation of tumor cells and perhaps tumor stem cells. Here, we will discuss GABAÃÂs presence as a near-universal signal that may be altered in tumor cells resulting in modified mitotic activity.

Stephanie Z. Young (Yale University Neurosurgery); Angélique Bordey (Yale University Neurosurgery)



Concentration-dependent effects of GABA on insensitivity to fipronil in the A2'S mutant RDL GABA receptor from fipronil-resistant Oulema oryzae (Coleoptera: Chrysomelidae).  


The beetle Oulema oryzae Kuwayama (Coleoptera: Chrysomelidae), an important pest of rice, has developed fipronil resistance in Japan. Molecular cloning and sequence analysis of O. oryzae RDL gamma-aminobutyric acid (GABA) receptor subunit (OO-RDL) genes from fipronil-susceptible and -resistant O. oryzae identified the A2'S mutation (index number for the M2 membrane-spanning region). To investigate the effect of the A2'S mutation on fipronil resistance, we stably expressed the wild-type and mutant OO-RDL homomers in Drosophila Mel-2 cells. A membrane potential assay exhibited that the IC50 values of fipronil for inhibition of the response to EC80 GABA of the wild-type and A2'S mutant OO-RDL homomers were 0.09 microM and 0.11 microM, respectively. However, the IC50 values of fipronil for inhibition of the response to EC95 GABA of the wild-type and A2'S mutant OO-RDL homomers were 0.11 microM and approximately equal to 5 microM, respectively. These results suggest that the GABA concentration is an important factor affecting fipronil resistance in O. oryzae carrying the A2'S mutation in OO-RDL. PMID:23156177

Nakao, Toshifumi; Naoi, Atsuko; Hama, Masako; Kawahara, Nobuyuki; Hirase, Kangetsu



Astrocytic Control of Biosynthesis and Turnover of the Neurotransmitters Glutamate and GABA  

PubMed Central

Glutamate and GABA are the quantitatively major neurotransmitters in the brain mediating excitatory and inhibitory signaling, respectively. These amino acids are metabolically interrelated and at the same time they are tightly coupled to the intermediary metabolism including energy homeostasis. Astrocytes play a pivotal role in the maintenance of the neurotransmitter pools of glutamate and GABA since only these cells express pyruvate carboxylase, the enzyme required for de novo synthesis of the two amino acids. Such de novo synthesis is obligatory to compensate for catabolism of glutamate and GABA related to oxidative metabolism when the amino acids are used as energy substrates. This, in turn, is influenced by the extent to which the cycling of the amino acids between neurons and astrocytes may occur. This cycling is brought about by the glutamate/GABA – glutamine cycle the operation of which involves the enzymes glutamine synthetase (GS) and phosphate-activated glutaminase together with the plasma membrane transporters for glutamate, GABA, and glutamine. The distribution of these proteins between neurons and astrocytes determines the efficacy of the cycle and it is of particular importance that GS is exclusively expressed in astrocytes. It should be kept in mind that the operation of the cycle is associated with movement of ammonia nitrogen between the two cell types and different mechanisms which can mediate this have been proposed. This review is intended to delineate the above mentioned processes and to discuss quantitatively their relative importance in the homeostatic mechanisms responsible for the maintenance of optimal conditions for the respective neurotransmission processes to operate. PMID:23966981

Schousboe, Arne; Bak, Lasse K.; Waagepetersen, Helle S.



Detection of the inhibitory neurotransmitter GABA in macrophages by magnetic resonance spectroscopy  

Microsoft Academic Search

Macrophages are key components of the inflammatory response to tissue injury, but their activities can exacerbate neuropathology. High-resolution magnetic resonance spectroscopy was used to identify metabolite levels in perchloric acid extracts of cultured cells of the RAW 264.7 murine macrophage line under resting and lipo- polysaccharide-activated conditions. Over 25 me- tabolites were identified including -aminobutyric acid (GABA), an inhibitory neurotransmitter

D. J. Stuckey; D. C. Anthony; J. P. Lowe; J. Miller; W. M. Palm; V. H. Perry; A. M. Blamire; N. R. Sibson



The benzodiazepine site of the GABA A receptor: an old target with new potential?  

Microsoft Academic Search

The gamma-aminobutyric acid-A (GABAA) receptors is the target for the most widely prescribed sleep medicines. It is a ligand-gated ion channel, activated by the amino acid neurotransmitter GABA, which normally results in hyperpolarization of neurons leading to reduced action potential firing, and thereby a reduction in neuronal activity. It has a rich pharmacology with a number of separate modulator binding

Alan N Bateson



Tolerance to the effects of diazepam, clonazepam and bretazenil on GABA-stimulated Cl- influx in flurazepam tolerant rats.  


The effect of chronic flurazepam treatment on the GABA (gamma-aminobutyric acid) receptor/chloride channel complex was studied using GABA-stimulated 36Cl- influx into brain microsacs, and its potentiation by diazepam, clonazepam and bretazenil. Rats were given flurazepam for 1 week, then microsacs were prepared from cerebral cortices of rats that were still receiving flurazepam, and from those that had stopped treatment 48 h earlier. Diazepam and clonazepam produced concentration-dependent increases in GABA-stimulated 36Cl- influx while bretazenil produced a much smaller effect, which did not reach statistical significance in the tissue from control rats. There was no significant change in the basal or 10 microM GABA-stimulated 36Cl- influx between control and treated groups. Tolerance was shown by a significantly reduced effect of diazepam and clonazepam to enhance GABA-stimulated 36Cl- influx in the tissue prepared from non-withdrawn rats. However, for both diazepam and clonazepam, there was no tolerance 48 h after chronic treatment. The results suggest that changes in the GABA receptor/Cl- channel complex on cerebral cortical neurons contribute to cross-tolerance from flurazepam to other benzodiazepines. PMID:8307102

Li, M; Rosenberg, H C; Chiu, T H



Selective distribution of GABA(A) receptor subtypes in mouse spinal dorsal horn neurons and primary afferents.  


In the spinal cord dorsal horn, presynaptic GABA(A) receptors (GABA(A)Rs) in the terminals of nociceptors as well as postsynaptic receptors in spinal neurons regulate the transmission of nociceptive and somatosensory signals from the periphery. GABA(A)Rs are heterogeneous and distinguished functionally and pharmacologically by the type of ? subunit variant they contain. This heterogeneity raises the possibility that GABA(A)R subtypes differentially regulate specific pain modalities. Here, we characterized the subcellular distribution of GABA(A)R subtypes in nociceptive circuits by using immunohistochemistry with subunit-specific antibodies combined with markers of primary afferents and dorsal horn neurons. Confocal laser scanning microscopy analysis revealed a distinct, partially overlapping laminar distribution of ?1-3 and ?5 subunit immunoreactivity in laminae I-V. Likewise, a layer-specific pattern was evident for their distribution among glutamatergic, ?-aminobutyric acid (GABA)ergic, and glycinergic neurons (detected in transgenic mice expressing vesicular glutamate transporter 2-enhanced green fluorescent protein [vGluT2-eGFP], glutamic acid decarboxylase [GAD]67-eGFP, and glycine transporter 2 (GlyT2)-eGFP, respectively). Finally, all four subunits could be detected within primary afferent terminals. C-fibers predominantly contained either ?2 or ?3 subunit immunoreactivity; terminals from myelinated (A?/A?) fibers were colabeled in roughly equal proportion with each subunit. The presence of axoaxonic GABAergic synapses was determined by costaining with gephyrin and vesicular inhibitory amino acid transporter to label GABAergic postsynaptic densities and terminals, respectively. Colocalization of the ?2 or ?3 subunit with these markers was observed in a subset of C-fiber synapses. Furthermore, gephyrin mRNA and protein expression was detected in dorsal root ganglia. Collectively, these results show that differential GABA(A)R distribution in primary afferent terminals and dorsal horn neurons allows for multiple, circuit-specific modes of regulation of nociceptive circuits. PMID:22522945

Paul, Jolly; Zeilhofer, Hanns Ulrich; Fritschy, Jean-Marc



Valerian Inhibits Rat Hepatocarcinogenesis by Activating GABA(A) Receptor-Mediated Signaling  

PubMed Central

Valerian is widely used as a traditional medicine to improve the quality of sleep due to interaction of several active components with the ?-aminobutyric acid (GABA) A receptor (GABA(A)R) system. Recently, activation of GABA signaling in stem cells has been reported to suppress cell cycle progression in vivo. Furthermore, possible inhibitory effects of GABA(A)R agonists on hepatocarcinogenesis have been reported. The present study was performed to investigate modulating effects of Valerian on hepatocarcinogenesis using a medium-term rat liver bioassay. Male F344 rats were treated with one of the most powerful Valerian species (Valeriana sitchensis) at doses of 0, 50, 500 and 5000 ppm in their drinking water after initiation of hepatocarcinogenesis with diethylnitrosamine (DEN). Formation of glutathione S-transferase placental form positive (GST-P+) foci was significantly inhibited by Valerian at all applied doses compared with DEN initiation control rats. Generation of 8-hydroxy-2?-deoxyguanosine in the rat liver was significantly suppressed by all doses of Valerian, likely due to suppression of Nrf2, CYP7A1 and induction of catalase expression. Cell proliferation was significantly inhibited, while apoptosis was induced in areas of GST-P+ foci of Valerian groups associated with suppression of c-myc, Mafb, cyclin D1 and induction of p21Waf1/Cip1, p53 and Bax mRNA expression. Interestingly, expression of the GABA(A)R alpha 1 subunit was observed in GST-P+ foci of DEN control rats, with significant elevation associated with Valerian treatment. These results indicate that Valerian exhibits inhibitory effects on rat hepatocarcinogenesis by inhibiting oxidative DNA damage, suppressing cell proliferation and inducing apoptosis in GST-P+ foci by activating GABA(A)R-mediated signaling. PMID:25419570

Kakehashi, Anna; Kato, Ayumi; Ishii, Naomi; Wei, Min; Morimura, Keiichirou; Fukushima, Shoji; Wanibuchi, Hideki



In Vivo Measurement of Brain GABA Concentrations by Magnetic Resonance Spectroscopy in Smelters Occupationally Exposed to Manganese  

PubMed Central

Background Exposure to excessive levels of manganese (Mn) is known to induce psychiatric and motor disorders, including parkinsonian symptoms. Therefore, finding a reliable means for early detection of Mn neurotoxicity is desirable. Objectives Our goal was to determine whether in vivo brain levels of ?-aminobutyric acid (GABA), N-acetylaspartate (NAA), and other brain metabolites in male smelters were altered as a consequence of Mn exposure. Methods We used T1-weighted magnetic resonance imaging (MRI) to visualize Mn deposition in the brain. Magnetic resonance spectroscopy (MRS) was used to quantify concentrations of NAA, glutamate, and other brain metabolites in globus pallidus, putamen, thalamus, and frontal cortex from a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. We used the MEGA-PRESS MRS sequence to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia [GABA-VOI (volume of interest)]. Results Seven of 10 exposed subjects showed clear T1-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p = 0.014) in the ratio of GABA to total creatine (GABA/tCr) in the GABA-VOI of Mn-exposed subjects, as well as a distinct decrease (9%; p = 0.04) of NAA/tCr in frontal cortex that strongly correlated with cumulative Mn exposure (R = ?0.93; p < 0.001). Conclusions We demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased NAA levels in the frontal cortex, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the noninvasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity. PMID:20876035

Dydak, Ulrike; Jiang, Yue-Ming; Long, Li-Ling; Zhu, He; Chen, Jian; Li, Wen-Mei; Edden, Richard A.E.; Hu, Shuguang; Fu, Xue; Long, Zaiyang; Mo, Xue-An; Meier, Dieter; Harezlak, Jaroslaw; Aschner, Michael; Murdoch, James B.; Zheng, Wei



Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones.  

PubMed Central

1. The effects of benzodiazepines and non-benzodiazepine compounds on the gamma-aminobutyric acid (GABA)-induced chloride current (ICl) were studied in frog isolated sensory neurones by use of a concentration-jump (termed 'concentration-clamp') technique, under single-electrode voltage-clamp conditions. The drugs used were classified into four categories as follows: full benzodiazepine receptor agonists (diazepam, clonazepam, nitrazepam, midazolam, clotiazepam and etizolam), partial agonists (CL 218,872, Ro 16-6028, Ro 17-1812 and Ro 23-0364), inverse agonists (Ro 15-3505, FG 7142 and beta-CCE) and a benzodiazepine receptor antagonist, Ro 15-1788 (flumazenil). 2. All full agonists at concentrations of 3 x 10(-6) M or less increased dose-dependently the peak amplitude of ICl elicited by 3 x 10(-6) M GABA to twice to three times larger than the control. However, no further augmentation of the GABA response was observed at concentrations of 1 x 10(-5) M or higher. Partial agonists also showed a dose-dependent augmentation of the GABA response at concentrations ranging from 3 x 10(-8) M to 3 x 10(-5) M, but their efficacies of augmentation of the GABA response were only about half or less of those of full agonists. Of the inverse agonists, beta-CCE had a unique dose-dependent effect on the GABA response. Beta-CCE reduced dose-dependently the GABA response at concentrations of less than 3 x 10(-6) M, but augmented it at concentrations of 3 x 10(-5) M and 6 x 10(-5) M. The inverse agonists reduced dose-dependently the GABA response.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2574062

Yakushiji, T.; Fukuda, T.; Oyama, Y.; Akaike, N.



GABA(B) receptors, schizophrenia and sleep dysfunction: a review of the relationship and its potential clinical and therapeutic implications.  


Evidence for an intrinsic relationship between sleep, cognition and the symptomatic manifestations of schizophrenia is accumulating. This review presents evidence for the possible utility of GABA(B) receptor agonists for the treatment of subjective and objective sleep abnormalities related to schizophrenia. At the phenotypic level, sleep disturbance occurs in 16-30% of patients with schizophrenia and is related to reduced quality of life and poor coping skills. On the neurophysiological level, studies suggest that sleep deficits reflect a core component of schizophrenia. Specifically, slow-wave sleep deficits, which are inversely correlated with cognition scores, are seen. Moreover, sleep plays an increasingly well documented role in memory consolidation in schizophrenia. Correlations of slow-wave sleep deficits with impaired reaction time and declarative memory have also been reported. Thus, both behavioural insomnia and sleep architecture are critical therapeutic targets in patients with schizophrenia. However, long-term treatment with antipsychotics often results in residual sleep dysfunction and does not improve slow-wave sleep, and adjunctive GABA(A) receptor modulators, such as benzodiazepines and zolpidem, can impair sleep architecture and cognition in schizophrenia. GABA(B) receptor agonists have therapeutic potential in schizophrenia. These agents have minimal effect on rapid eye movement sleep while increasing slow-wave sleep. Preclinical associations with increased expression of genes related to slow-wave sleep production and circadian rhythm function have also been reported. GABA(B) receptor deficits result in a sustained hyperdopaminergic state and can be reversed by a GABA(B) receptor agonist. Genetic, postmortem and electrophysiological studies also associate GABA(B) receptors with schizophrenia. While studies thus far have not shown significant effects, prior focus on the use of GABA(B) receptor agonists has been on the positive symptoms of schizophrenia, with minimal investigation of GABA(B) receptor agonists such as baclofen or gamma-hydroxybutyric acid and their effects on sleep architecture, cognition and negative symptoms in patients with schizophrenia. Further study is needed. PMID:19594197

Kantrowitz, Joshua; Citrome, Leslie; Javitt, Daniel



Brain GABA and glutamate levels in workers of two ant species (Hymenoptera: Formicidae): Interspecific differences and effects of queen presence/absence.  


Presence of amino acid neurotransmitters gamma-aminobutyric acid (GABA) and glutamate (Glu) in ant brains was reported in very few studies. To learn more about factors influencing GABA and Glu levels in ant brains, we applied high-performance liquid chromatography to measure levels of these compounds in single brains of workers of 2 ant species, Myrmica ruginodis (subfamily Myrmicinae) and Formica polyctena (subfamily Formicinae) taken from queenright/queenless colony fragments and tested in dyadic aggression tests consisting of an encounter with a nestmate, an alien conspecific or a small cricket. Brain glutamate levels were higher than those of GABA in both tested species. Brain GABA levels (in ?mol/brain) and GABA : Glu ratio were higher in M. ruginodis (a submissive species) than in F. polyctena (a dominant, aggressive species) in spite of smaller brain weight of M. ruginodis. Brain glutamate levels (in ?mol/brain) did not differ between the tested species, which implies that glutamate concentration (in ?mol/mg of brain tissue) was higher in M. ruginodis. Queen absence was associated with increased worker brain GABA levels in F. polyctena, but not in M. ruginodis. No significant effects of opponent type were discovered. As GABA agonists enhance friendly social behavior in rodents, we hypothesize that elevated brain GABA levels of orphaned workers of F. polyctena facilitate the adoption of a new queen. This is the first report providing information on GABA and glutamate levels in single ant brains and documenting the effects of queen presence/absence on brain levels of amino acid neurotransmitters in workers of social Hymenoptera. PMID:24174300

Wnuk, Andrzej; Kostowski, Wojciech; Korczy?ska, Julita; Szczuka, Anna; Symonowicz, Beata; Bie?kowski, Przemys?aw; Mierzejewski, Pawe?; Godzi?ska, Ewa Joanna



Colocalization of synaptic GABA(C)-receptors with GABA (A)-receptors and glycine-receptors in the rodent central nervous system.  


Fast inhibition in the nervous system is preferentially mediated by GABA- and glycine-receptors. Two types of ionotropic GABA-receptor, the GABA(A)-receptor and GABA(C)-receptor, have been identified; they have specific molecular compositions, different sensitivities to GABA, different kinetics, and distinct pharmacological profiles. We have studied, by immunocytochemistry, the synaptic localization of glycine-, GABA(A)-, and GABA(C)-receptors in rodent retina, spinal cord, midbrain, and brain-stem. Antibodies specific for the alpha1 subunit of the glycine-receptor, the gamma2 subunit of the GABA(A)-receptor, and the rho subunits of the GABA(C)-receptor have been applied. Using double-immunolabeling, we have determined whether these receptors are expressed at the same postsynaptic sites. In the retina, no such colocalization was observed. However, in the spinal cord, we found the colocalization of glycine-receptors with GABA(A)- or GABA(C)-receptors and the colocalization of GABA(A)- and GABA(C)-receptors in approximately 25% of the synapses. In the midbrain and brain-stem, GABA(A)- and GABA(C)-receptors were colocalized in 10%-15% of the postsynaptic sites. We discuss the possible expression of heteromeric (hybrid) receptors assembled from GABA(A)- and GABA(C)-receptor subunits. Our results suggest that GABA(A)- and GABA(C)-receptors are colocalized in a minority of synapses of the central nervous system. PMID:17610086

Frazao, Renata; Nogueira, Maria Ines; Wässle, Heinz



R-(-)-beta-phenyl-GABA is a full agonist at GABAB receptors in brain slices but a partial agonist in the ileum.  


R-(-)-beta-phenyl-GABA has been compared at GABAB receptors using cortical and ileal preparations. R-(-)-beta-phenyl-GABA (EC50 = 25 microM) was a less potent full agonist than R,S-(+/-)-baclofen (EC50 = 2.5 microM), in depressing CA1 population spikes of rat hippocampal slices, and 5 times less potent in attenuating the spontaneous discharges of rat neocortex. However, R-(-)-beta-phenyl-GABA (100-400 microM) was only a weak partial agonist in the ileum. All these actions were sensitive to CGP 35348 (3-aminopropyl-(P-diethoxymethyl)-phosphinic acid) and therefore mediated by GABAB receptors. PMID:8386087

Ong, J; Kerr, D I; Doolette, D J; Duke, R K; Mewett, K N; Allen, R D; Johnston, G A



Isothiouronium compounds as gamma-aminobutyric acid agonists.  

PubMed Central

Analogues of gamma-aminobutyric acid (GABA) incorporating an isothiouronium salt as a replacement for a protonated amino functional group have been investigated for activity on: GABA receptors in the guinea-pig ileum; [3H]-GABA and [3H]-diazepam binding to rat brain membranes; and GABA uptake and transamination. For the homologous series of omega-isothiouronium alkanoic acids, maximum GABA-mimetic activity was found at 3-[(aminoiminomethyl)thio]propanoic acid. Introduction of unsaturation into this compound gave two isomeric conformationally restricted analogues. The trans isomer was inactive at GABA receptors while the cis compound ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA)) was more potent than muscimol and GABA as a GABA agonist with respect to low affinity GABA receptor sites. Both isomers were moderately potent at inhibiting the uptake of [3H]-GABA into rat brain slices. Comparison of possible conformations of the two unsaturated isomers by interactive computer graphics modelling and comparison with muscimol has led to a plausible active conformation of ZAPA, which may be a selective and potent agonist for low affinity GABA binding sites. PMID:3015310

Allan, R. D.; Dickenson, H. W.; Hiern, B. P.; Johnston, G. A.; Kazlauskas, R.



GABA{sub A} receptor open-state conformation determines non-competitive antagonist binding  

SciTech Connect

The {gamma}-aminobutyric acid (GABA) type A receptor (GABA{sub A}R) is one of the most important targets for insecticide action. The human recombinant {beta}3 homomer is the best available model for this binding site and 4-n-[{sup 3}H]propyl-4'-ethynylbicycloorthobenzoate ([{sup 3}H]EBOB) is the preferred non-competitive antagonist (NCA) radioligand. The uniquely high sensitivity of the {beta}3 homomer relative to the much-less-active but structurally very-similar {beta}1 homomer provides an ideal comparison to elucidate structural and functional features important for NCA binding. The {beta}1 and {beta}3 subunits were compared using chimeragenesis and mutagenesis and various combinations with the {alpha}1 subunit and modulators. Chimera {beta}3/{beta}1 with the {beta}3 subunit extracellular domain and the {beta}1 subunit transmembrane helices retained the high [{sup 3}H]EBOB binding level of the {beta}3 homomer while chimera {beta}1/{beta}3 with the {beta}1 subunit extracellular domain and the {beta}3 subunit transmembrane helices had low binding activity similar to the {beta}1 homomer. GABA at 3 {mu}M stimulated heteromers {alpha}1{beta}1 and {alpha}1{beta}3 binding levels more than 2-fold by increasing the open probability of the channel. Addition of the {alpha}1 subunit rescued the inactive {beta}1/{beta}3 chimera close to wildtype {alpha}1{beta}1 activity. EBOB binding was significantly altered by mutations {beta}1S15'N and {beta}3N15'S compared with wildtype {beta}1 and {beta}3, respectively. However, the binding activity of {alpha}1{beta}1S15'N was insensitive to GABA and {alpha}1{beta}3N15'S was stimulated much less than wildtype {alpha}1{beta}3 by GABA. The inhibitory effect of etomidate on NCA binding was reduced more than 5-fold by the mutation {beta}3N15'S. Therefore, the NCA binding site is tightly regulated by the open-state conformation that largely determines GABA{sub A} receptor sensitivity. - Graphical Abstract: Display Omitted Research Highlights: > The {beta}1 and {beta}3 subunits were compared by chimeragenesis, mutagenesis and modulators. > Low {beta}1 NCA binding was rescued by replacing its transmembrane helices with those of {beta}3. > GABA at 3 {mu}M stimulated heteromers {alpha}1{beta}1 and {alpha}1{beta}3 binding levels more than 2-fold. > Mutation at 15' position in TM2 reduced GABA stimulation of NCA binding. > The open-state conformation largely determines GABAA receptor sensitivity to NCAs.

Chen Ligong [Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720 (United States); Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158 (United States); Xue Ling [Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 (United States); Giacomini, Kathleen M. [Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158 (United States); Casida, John E., E-mail: [Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720 (United States)



Agonist- and antagonist-induced conformational changes of loop F and their contributions to the ?1 GABA receptor function  

PubMed Central

Binding of ?-aminobutyric acid (GABA) to its receptor initiates a conformational change to open the channel, but the mechanism of the channel activation is not well understood. To this end, we scanned loop F (K210–F227) in the N-terminal domain of the ?1 GABA receptor expressed in Xenopus oocytes using a site-specific fluorescence technique. We detected GABA-induced fluorescence changes at six positions (K210, K211, L216, K217, T218 and I222). At these positions the fluorescence changes were dose dependent and highly correlated to the current dose–response, but with lower Hill coefficients. The competitive antagonist 3-aminopropyl(methyl)phosphinic acid (3-APMPA) induced fluorescence changes in the same direction at the four middle or lower positions. The non-competitive antagonist picrotoxin blocked nearly 50% of GABA-induced fluorescence changes at T218 and I222, but only <20% at K210 and K217 and 0% at K211 and L216 positions. Interestingly, the picrotoxin-blocked fraction of the GABA-induced fluorescence changes was highly correlated to the Hill coefficient of the GABA-induced dose-dependent fluorescence change. The PTX-insensitive mutant L216C exhibited the lowest Hill coefficient, similar to that in binding. Thus, the PTX-sensitive fraction reflects the conformational change related to channel gating, whereas the PTX-insensitive fraction represents a binding effect. The binding effect is further supported by the picrotoxin resistance of a competitive antagonist-induced fluorescence change. A cysteine accessibility test further confirmed that L216C and K217C partially line the binding pocket, and I222C became more exposed by GABA. Our results are consistent with a mechanism that an outward movement of the lower part of loop F is coupled to the channel activation. PMID:19015197

Zhang, Jianliang; Xue, Fenqin; Chang, Yongchang



Prebiotic syntheses of vitamin coenzymes: II. Pantoic acid, pantothenic acid, and the composition of coenzyme A  

NASA Technical Reports Server (NTRS)

Pantoic acid can by synthesized in good prebiotic yield from isobutyraldehyde or alpha-ketoisovaleric acid + H2CO + HCN. Isobutyraldehyde is the Strecker precursor to valine and alpha-ketoisovaleric acid is the valine transamination product. Mg2+ and Ca2+ as well as several transition metals are catalysts for the alpha-ketoisovaleric acid reaction. Pantothenic acid is produced from pantoyl lactone (easily formed from pantoic acid) and the relatively high concentrations of beta-alanine that would be formed on drying prebiotic amino acid mixtures. There is no selectivity for this reaction over glycine, alanine, or gamma-amino butyric acid. The components of coenzyme A are discussed in terms of ease of prebiotic formation and stability and are shown to be plausible choices, but many other compounds are possible. The gamma-OH of pantoic acid needs to be capped to prevent decomposition of pantothenic acid. These results suggest that coenzyme A function was important in the earliest metabolic pathways and that the coenzyme A precursor contained most of the components of the present coenzyme.

Miller, S. L.; Schlesinger, G.



Conformationally Restricted GABA with Bicyclo[3.1.0]hexane Backbone as the First Highly Selective BGT-1 Inhibitor.  


On the basis of the three-dimensional diversity-oriented conformational restriction strategy using key chiral cyclopropane units, we previously identified 3 ((2S,3R)-4-amino-3,4-methanobutyric acid) with a chiral trans-cyclopropane structure as a ?-aminobutyric acid (GABA) transporter inhibitor selective for GABA transporter (GAT) subtypes GAT-3 and BGT-1 (betaine/GABA transporter-1). Further conformational restriction of 3 with the rigid bicyclo[3.1.0]hexane backbone led to the successful development of the first highly potent and selective BGT-1 inhibitor 4 (IC50 = 0.59 ?M). The bioactive conformation of 3 for BGT-1 was also identified. PMID:25147609

Kobayashi, Takaaki; Suemasa, Akihiro; Igawa, Arisa; Ide, Soichiro; Fukuda, Hayato; Abe, Hiroshi; Arisawa, Mitsuhiro; Minami, Masabumi; Shuto, Satoshi



The contribution of GABA to glutamate/glutamine cycling and energy metabolism in the rat cortex in vivo  

PubMed Central

Previous studies have shown that the glutamate/glutamine (Glu/Gln) neurotransmitter cycle and neuronal glucose oxidation are proportional (1:1), with increasing neuronal activity above isoelectricity. GABA, a product of Glu metabolism, is synthesized from astroglial Gln and contributes to total Glu/Gln neurotransmitter cycling, although the fraction contributed by GABA is unknown. In the present study, we used 13C NMR spectroscopy together with i.v. infusions of [1,6-13C2]glucose and [2-13C]acetate to separately determine rates of Glu/Gln and GABA/Gln cycling and their respective tricarboxylic acid cycles in the rat cortex under conditions of halothane anesthesia and pentobarbital-induced isoelectricity. Under 1% halothane anesthesia, GABA/Gln cycle flux comprised 23% of total (Glu plus GABA) neurotransmitter cycling and 18% of total neuronal tricarboxylic acid cycle flux. In isoelectric cortex, glucose oxidation was reduced >3-fold in glutamatergic and GABAergic neurons, and neurotransmitter cycling was below detection. Hence, in both cell types, the primary energetic costs are associated with neurotransmission, which increase together as cortical activity is increased. The contribution of GABAergic neurons and inhibition to cortical energy metabolism has broad implications for the interpretation of functional imaging signals. PMID:15809416

Patel, Anant B.; de Graaf, Robin A.; Mason, Graeme F.; Rothman, Douglas L.; Shulman, Robert G.; Behar, Kevin L.



Evidence for GABA involvement in stress-induced inhibition of male amphibian sexual behavior.  


The behavioral effects of GABA analogs were investigated to determine whether GABAergic neurotransmission is involved in the stress-induced inhibition of masculine sexual behaviors in rough-skinned newts (Taricha granulosa). Injections of bicuculline, a GABA antagonist, stimulated male sexual behaviors in a dose-dependent fashion, and the minimum effective dose was 40-fold less when administered centrally rather than systemically, suggesting a central nervous system site of action. Injections of muscimol, a GABA agonist, suppressed reproductive behaviors in male newts, and this inhibition lasted at least 5 hr and was proportional to the dose of muscimol administered. The inhibitory effects of muscimol on newt sexual behaviors could be reversed by a single 100-microgram ip injection of arginine vasotocin. The inhibitory effects of confinement stress or corticosterone (CS) injections on newt sexual behaviors were blocked by pretreatment of newts with mercaptopropionic acid, a blocker of GABA synthesis. As well, bicuculline prevented the inhibition of sexual behavior induced by CS injection. These results support the conclusion that, in a male amphibian, the GABAergic system is involved in the inhibitory mechanisms regulating sexual behaviors and that CS mediates the stress-induced inhibition of sexual behaviors through the GABAergic system. PMID:2158482

Boyd, S K; Moore, F L



Identification of gamma-aminobutyric acid and its binding sites in Caenorhabditis elegans  

SciTech Connect

Gamma-aminobutyric acid (GABA), glutamate decarboxylase and GABA-transaminase were identified in the nematode Caenorhabditis elegans. The concentration of GABA in C. elegans is approximately 10-fold lower than the concentration of GABA in rat brain. Glutamate decarboxylase and GABA-transaminase, the GABA anabolic and catabolic enzymes, are also present in C. elegans. Crude membrane fractions were prepared from C. elegans and used to study specific (/sup 3/H) GABA binding sites. GABA binds to C. elegans membranes with high affinity and low capacity. Muscimol is a competitive inhibitor of specific GABA binding with a K/sub I/ value of 120 nM. None of the other GABA agonists or antagonists inhibited greater than 40% of the specific GABA binding at concentrations up to 10/sup -4/M. Thirteen spider venoms were examined as possible GABA agonists or antagonists, the venom from Calilena agelenidae inhibits specific GABA binding with a K/sub I/ value of 6 nl/ml. These results suggest that GABA has a physiological role as a neurotransmitter in C. elegans.

Schaeffer, J.M.; Bergstrom, A.R.



Specific targeting of the GABA-A receptor ?5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice  

PubMed Central

An imbalance between inhibitory and excitatory neurotransmission has been proposed to contribute to altered brain function in individuals with Down syndrome (DS). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and accordingly treatment with GABA-A antagonists can efficiently restore cognitive functions of Ts65Dn mice, a genetic model for DS. However, GABA-A antagonists are also convulsant which preclude their use for therapeutic intervention in DS individuals. Here, we have evaluated safer strategies to release GABAergic inhibition using a GABA-A-benzodiazepine receptor inverse agonist selective for the ?5-subtype (?5IA). We demonstrate that ?5IA restores learning and memory functions of Ts65Dn mice in the novel-object recognition and in the Morris water maze tasks. Furthermore, we show that following behavioural stimulation, ?5IA enhances learning-evoked immediate early gene products in specific brain regions involved in cognition. Importantly, acute and chronic treatments with ?5IA do not induce any convulsant or anxiogenic effects that are associated with GABA-A antagonists or non-selective inverse agonists of the GABA-A-benzodiazepine receptors. Finally, chronic treatment with ?5IA did not induce histological alterations in the brain, liver and kidney of mice. Our results suggest that non-convulsant ?5-selective GABA-A inverse agonists could improve learning and memory deficits in DS individuals. PMID:21693554

Braudeau, J; Delatour, B; Duchon, A; Pereira, P Lopes; Dauphinot, L; de Chaumont, F; Olivo-Marin, J-C; Dodd, RH; Herault, Y; Potier, M-C



Influence of GABA on gonadotrophin release in the goldfish.  


The influence of GABA on pituitary gonadotrophin (GTH) release in the goldfish was studied by means of in vivo and in vitro techniques. It was found that GABA injected intraperitoneally caused an increase of serum GTH levels in regressed or early maturing fish, but not in late maturing animals. Moreover, injection of a GABA transaminase inhibitor caused a significant increase of GABA within the hypothalamus and pituitary, and a dose-dependent increase in serum GTH levels. To determine if this effect could be exerted directly at the level of the pituitary, dispersed pituitary cells in static incubation or in perifusion were exposed to increasing concentrations of GABA or its agonists muscimol and baclofen. None of these drugs was able to modify the spontaneous or GnRH-induced secretion of GTH, indicating that the in vivo effect of GABA was most likely mediated via another hypothalamic factor. Using in vitro incubation of pituitary slices, it was found that GABA caused a dose-related stimulation of GnRH release at the level of the pituitary, providing a possible explanation for the observed in vivo stimulatory effect of GABA on GTH release. Since the seasonal effect of GABA in vivo indicated a possible interaction of GABA with sexual steroids, GABA was given intraperitoneally to female goldfish implanted with either testosterone or estradiol. We found that the stimulatory effect of GABA on GTH release was abolished in estradiol-treated females but was still observed in testosterone-implanted fish. Moreover, estradiol but not testosterone caused a decrease of the GABA concentration within the telencephalon.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1565206

Kah, O; Trudeau, V L; Sloley, B D; Chang, J P; Dubourg, P; Yu, K L; Peter, R E



P2Y1 receptor inhibits GABA transport through a calcium signalling-dependent mechanism in rat cortical astrocytes.  


Astrocytes express a variety of purinergic (P2) receptors, involved in astrocytic communication through fast increases in [Ca(2+) ]i . Of these, the metabotropic ATP receptors (P2Y) regulate cytoplasmic Ca(2+) levels through the PLC-PKC pathway. GABA transporters are a substrate for a number of Ca(2+) -related kinases, raising the possibility that calcium signalling in astrocytes impact the control of extracellular levels of the major inhibitory transmitter in the brain. To access this possibility we tested the influence of P2Y receptors upon GABA transport into astrocytes. Mature primary cortical astroglial-enriched cultures expressed functional P2Y receptors, as evaluated through Ca(2+) imaging, being P2Y1 the predominant P2Y receptor subtype. ATP (100 ?M, for 1 min) caused an inhibition of GABA transport through either GAT-1 or GAT-3 transporters, decreasing the Vmax kinetic constant. ATP-induced inhibition of GATs activity was still evident in the presence of adenosine deaminase, precluding an adenosine-mediated effect. This, was mimicked by a specific agonist for the P2Y1,12,13 receptor (2-MeSADP). The effect of 2-MeSADP on GABA transport was blocked by the P2 (PPADS) and P2Y1 selective (MRS2179) receptor antagonists, as well as by the PLC inhibitor (U73122). 2-MeSADP failed to inhibit GABA transport in astrocytes where intracellular calcium had been chelated (BAPTA-AM) or where calcium stores were depleted (?-cyclopiazonic acid, CPA). In conclusion, P2Y1 receptors in astrocytes inhibit GABA transport through a mechanism dependent of P2Y1 -mediated calcium signalling, suggesting that astrocytic calcium signalling, which occurs as a consequence of neuronal firing, may operate a negative feedback loop to enhance extracellular levels of GABA. PMID:24733747

Jacob, Pedro F; Vaz, Sandra H; Ribeiro, Joaquim A; Sebastião, Ana M



Comment on "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring".  


Tyzio et al. (Reports, 7 February 2014, p. 675) reported that bumetanide restored the impaired oxytocin-mediated ?-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery in animal models of autism, ameliorating some autistic-like characteristics in the offspring. However, standard practices in the study of these models, such as the use of sex-dimorphic or males-only analyses and implementation of tests measuring social behavior, are lacking to definitely associate their findings to autism. PMID:25301610

Bambini-Junior, Victorio; Nunes, Gustavo Della Flora; Schneider, Tomasz; Gottfried, Carmem



Reduced Expression of GABA Transporter GAT3 in Helpless Rats, an Animal Model of Depression  

Microsoft Academic Search

Mood disorders have been linked to glial and synaptic pathology such as disturbed neurotransmission of ?-aminobutyric acid\\u000a (GABA). We evaluated the expression of GABAergic marker genes in rats with helpless behaviour, an animal model of depression.\\u000a Male Sprague-Dawley rats from inbred lines were tested for helpless behaviour and grouped according to failures in terminating\\u000a foot shock currents. Expression levels of

M. Zink; B. Vollmayr; P. J. Gebicke-Haerter; F. A. Henn



Two-color, two-photon uncaging of glutamate and GABA.  


We developed a caged GABA (gamma-aminobutyric acid), which, when combined with an appropriate caged glutamate, allows bimodal control of neuronal membrane potential with subcellular resolution using optically independent two-photon uncaging of each neurotransmitter. We used two-color, two-photon uncaging to fire and block action potentials from rat hippocampal CA1 neurons in brain slices with 720-nm and 830-nm light, respectively. Our method should be generalizable to other chemical messenger pairs. PMID:20037590

Kantevari, Srinivas; Matsuzaki, Masanori; Kanemoto, Yuya; Kasai, Haruo; Ellis-Davies, Graham C R



An RNAi screen identifies genes that regulate GABA synapses.  


GABA synapses play a critical role in many aspects of circuit development and function. For example, conditions that perturb GABA transmission have been implicated in epilepsy. To identify genes that regulate GABA transmission, we performed an RNAi screen for genes whose inactivation increases the activity of C. elegans body muscles, which receive direct input from GABAergic motor neurons. We identified 90 genes, 21 of which were previously implicated in seizure syndromes, suggesting that this screen has effectively identified candidate genes for epilepsy. Electrophysiological recordings and imaging of excitatory and inhibitory synapses indicate that several genes alter muscle activity by selectively regulating GABA transmission. In particular, we identify two humoral pathways and several protein kinases that modulate GABA transmission but have little effect on excitatory transmission at cholinergic neuromuscular junctions. Our data suggest these conserved genes are components of signaling pathways that regulate GABA transmission and consequently may play a role in epilepsy and other cognitive or psychiatric disorders. PMID:18466746

Vashlishan, Amy B; Madison, Jon M; Dybbs, Mike; Bai, Jihong; Sieburth, Derek; Ch'ng, Queelim; Tavazoie, Masoud; Kaplan, Joshua M



Synthesis of  -Aminobutyric Acid by Lactic Acid Bacteria Isolated from a Variety of Italian Cheeses  

Microsoft Academic Search

The concentrations of -aminobutyric acid (GABA) in 22 Italian cheese varieties that differ in several technological traits markedly varied from 0.26 to 391 mg kg1. Presumptive lactic acid bacteria were isolated from each cheese variety (total of 440 isolates) and screened for the capacity to synthesize GABA. Only 61 isolates showed this activity and were identified by partial sequencing of

S. Siragusa; M. De Angelis; R. Di Cagno; C. G. Rizzello; R. Coda; M. Gobbetti



Response to Comment on "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring".  


Bambini-Junior et al. questioned whether our treatment in two rodent models of autism has a long-lasting effect into adulthood. In response, we show that bumetanide treatment around delivery attenuates autistic behavioral features in adult offspring. Therefore, the polarity of ?-aminobutyric acid (GABA) actions during delivery exerts long-lasting priming actions after birth. PMID:25301611

Eftekhari, Sanaz; Shahrokhi, Amene; Tsintsadze, Vera; Nardou, Romain; Brouchoud, Corinne; Conesa, Magali; Burnashev, Nail; Ferrari, Diana C; Ben-Ari, Yehezkel



Increased GABA Contributes to Enhanced Control over Motor Excitability in Tourette Syndrome  

PubMed Central

Summary Tourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics [1] and associated with cortical-striatal-thalamic-cortical circuit dysfunction [2, 3], hyperexcitability within cortical motor areas [4], and altered intracortical inhibition [4–7]. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals [1], who exhibit enhanced control over their volitional movements [8–11]. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability [6, 7, 12, 13]. Here we present a neurochemical basis for a localized gain control mechanism. We used ultra-high-field (7 T) magnetic resonance spectroscopy to investigate in vivo concentrations of ?-aminobutyric acid (GABA) within primary and secondary motor areas of individuals with TS. We demonstrate that GABA concentrations within the supplementary motor area (SMA)—a region strongly associated with the genesis of motor tics in TS [14]—are paradoxically elevated in individuals with TS and inversely related to fMRI blood oxygen level-dependent activation. By contrast, GABA concentrations in control sites do not differ from those of a matched control group. Importantly, we also show that GABA concentrations within the SMA are inversely correlated with cortical excitability in primary motor cortex and are predicted by motor tic severity and white-matter microstructure (FA) within a region of the corpus callosum that projects to the SMA within each hemisphere. Based upon these findings, we propose that extrasynaptic GABA contributes to a form of control, based upon localized tonic inhibition within the SMA, that may lead to the suppression of tics. PMID:25264251

Draper, Amelia; Stephenson, Mary C.; Jackson, Georgina M.; Pepes, Sophia; Morgan, Paul S.; Morris, Peter G.; Jackson, Stephen R.



Prenatal Nicotine Exposure Increases GABA Signaling and Mucin Expression in Airway Epithelium  

PubMed Central

Maternal smoking during pregnancy increases the risk of respiratory disease in offspring, but surprisingly little is known about the underlying mechanisms. Nicotinic acetylcholine receptors (nAChRs) expressed in bronchial epithelial cells (BECs) mediate the effects of nicotine on lung development and function. Recently, BECs were also shown to express a GABAergic paracrine loop that was implicated in mucus overproduction in asthma. We therefore investigated the interactions between cholinergic and GABAergic signaling in rhesus macaque BECs, and found that nicotine upregulated GABA signaling in BECs through the sequential activation of BEC nAChR and GABA receptors. The incubation of primary cultures of rhesus BECs increased concentrations of GAD, GABAA receptors, and mucin mRNA. The nicotine-induced increase in glutamatic acid decarboxylase (GAD) and GABAA receptor mRNA resulted in increased GABA-induced currents and increased expression of mucin. The ability of nicotine to increase mucin expression was blocked by nicotinic and GABAA antagonists. These results implicate GABA signaling as a middleman in nicotine's effects on mucus overproduction. Similar effects of nicotine on GABA signaling and the expression of mucin were seen in vivo after chronic exposure of rhesus monkeys to nicotine. These data provide a new mechanism linking smoking with the increased mucin seen in asthma and chronic obstructive pulmonary disorder, and suggest a new paradigm of communication between non-neuronal transmitter systems in BECs. The existence of neural-like transmitter interactions in BECs suggests that some drugs active in the central nervous system may possess previously unexpected utility in respiratory diseases. PMID:20448051

Fu, Xiao Wen; Wood, Kelsey; Spindel, Eliot R.



Increased GABA Contributes to Enhanced Control over Motor Excitability in Tourette Syndrome.  


Tourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics [1] and associated with cortical-striatal-thalamic-cortical circuit dysfunction [2, 3], hyperexcitability within cortical motor areas [4], and altered intracortical inhibition [4-7]. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals [1], who exhibit enhanced control over their volitional movements [8-11]. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability [6, 7, 12, 13]. Here we present a neurochemical basis for a localized gain control mechanism. We used ultra-high-field (7 T) magnetic resonance spectroscopy to investigate in vivo concentrations of ?-aminobutyric acid (GABA) within primary and secondary motor areas of individuals with TS. We demonstrate that GABA concentrations within the supplementary motor area (SMA)-a region strongly associated with the genesis of motor tics in TS [14]-are paradoxically elevated in individuals with TS and inversely related to fMRI blood oxygen level-dependent activation. By contrast, GABA concentrations in control sites do not differ from those of a matched control group. Importantly, we also show that GABA concentrations within the SMA are inversely correlated with cortical excitability in primary motor cortex and are predicted by motor tic severity and white-matter microstructure (FA) within a region of the corpus callosum that projects to the SMA within each hemisphere. Based upon these findings, we propose that extrasynaptic GABA contributes to a form of control, based upon localized tonic inhibition within the SMA, that may lead to the suppression of tics. PMID:25264251

Draper, Amelia; Stephenson, Mary C; Jackson, Georgina M; Pépés, Sophia; Morgan, Paul S; Morris, Peter G; Jackson, Stephen R



Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABA(A) receptors supports an allosteric model of modulation.  


Benzodiazepines (BZDs) have been used extensively for more than 40 years because of their high therapeutic index and low toxicity. Although BZDs are understood to act primarily as allosteric modulators of GABA(A) receptors, the mechanism of modulation is not well understood. The applicability of an allosteric model with two binding sites for gamma-aminobutyric acid (GABA) and one for a BZD-like modulator was investigated. This model predicts that BZDs should enhance the efficacy of partial agonists. Consistent with this prediction, diazepam increased the efficacy of the GABA(A) receptor partial agonist kojic amine in chick spinal cord neurons. To further test the validity of the model, the effects of diazepam, flurazepam, and zolpidem were examined using wild-type and spontaneously active mutant alpha1(L263S)beta3gamma2 GABA(A) receptors expressed in HEK-293 cells. In agreement with the predictions of the allosteric model, all three modulators acted as direct agonists for the spontaneously active receptors. The results indicate that BZD-like modulators enhance the amplitude of the GABA response by stabilizing the open channel active state relative to the inactive state by less than 1 kcal, which is similar to the energy of stabilization conferred by a single hydrogen bond. PMID:15912137

Downing, Scott S; Lee, Yan T; Farb, David H; Gibbs, Terrell T



GABA-mediated attenuation of noradrenaline release in the rat median preoptic area caused by intravenous injection of metaraminol.  


Previous studies have shown that the noradrenergic system in the median preoptic nucleus (MnPO) play an important role in the control of the body fluid balance and cardiovascular function and that the release of noradrenaline in the MnPO is regulated by gamma-aminobutyric acid (GABA) receptor mechanisms. The present study was carried out to examine whether the GABAergic system is involved in the modulation of the noradrenaline release in the MnPO in response to an elevation in blood pressure using in vivo microdialysis techniques. In urethane-anaesthetised male rats, the rise in arterial pressure caused by intravenous administration of the alpha-agonist metaraminol significantly decreased dialysate noradrenaline concentration in the MnPO area. The decrease in the noradrenaline level elicited by the metaraminol administration was significantly attenuated by perfusion with either bicuculline (10 microM), a GABA(A) receptor antagonist, or phaclofen (10 microM), a GABA(B) receptor antagonist, through a microdialysis probe. The amount of the antagonist-induced attenuation was much greater in the bicuculline-treated group than in the phaclofen-treated group. These results suggest that the release of noradrenaline in the MnPO area may be modulated by neural inputs from the peripheral baroreceptors, and that the neural inputs may be mediated in part through GABA(A) receptors rather than GABA(B) receptors in the MnPO area. PMID:15109934

Sakamaki, Kazuhiro; Nomura, Masahiko; Yamato, Koichi; Tanaka, Junichi



Medications acting on the GABA system in the treatment of alcoholic patients.  


Gamma aminobutyric acid (GABA) represents the major inhibitory neurotransmitter of the central nervous system. Ethanol as well as benzodiazepines (BDZs) and some anticonvulsant drugs directly affect GABAA receptors inducing similar anxiolytic, sedativehypnotic, and anticonvulsant effects. Since BDZs have proven their efficacy in ameliorating symptoms and in decreasing the risk of seizures and delirium tremens, they are the drugs of choice for the treatment of alcohol withdrawal syndrome (AWS). However, due to their addictive potential and lack of safety when combined with alcohol, BDZs are usually not recommended for the maintenance of alcohol abstinence. Other GABA-ergic medications represent potentially promising drugs useful in the treatment of AWS and in maintaining alcohol abstinence. Indeed, available studies have demonstrated that clomethiazole, gabapentin and gamma hydroxybutyrate (GHB) present a similar efficacy to BDZs in suppressing AWS. In addition, current evidence also indicates that gabapentin and GHB do not have significant interactions with ethanol that render them safe to use in maintaining alcohol abstinence. Moreover, gabapentin and valproic acid may be beneficial in maintaining alcohol abstinence in alcoholics with psychiatric co-morbidity. Pregabalin, neurosteroids, tiagabine, and vigabatrin need further clinical evidence of efficacy, safety and tolerability. Thus, given the importance of GABA-ergic mechanisms in the development and maintenance of alcohol dependence, and the very interesting results currently achieved, more research on GABAergic agents is warranted. PMID:20482512

Caputo, Fabio; Bernardi, Mauro




PubMed Central

Morphine, a ?-opioid receptor agonist, is a commonly prescribed treatment for pain. Although highly efficacious, morphine has many unwanted side effects including disruption of sleep and obtundation of wakefulness. One mechanism by which morphine alters sleep and wakefulness may be by modulating GABAergic signaling in brain regions regulating arousal, including the oral pontine reticular formation (PnO). This study used in vivo microdialysis in unanesthetized Sprague-Dawley rat to test the hypothesis that ?-opioid receptors modulate PnO GABA levels. Validation of the high performance liquid chromatographic technique used to quantify GABA was obtained by dialyzing the PnO (n=4 rats) with the GABA reuptake inhibitor nipecotic acid (500 ?M). Nipecotic acid caused a 185±20% increase in PnO GABA levels, confirming chromatographic detection of GABA and demonstrating the existence of functional GABA transporters in rat PnO. Morphine caused a concentration-dependent decrease in PnO GABA levels (n=25 rats). Coadministration of morphine (100 ?M) with naloxone (1 ?M), a ?-opioid receptor antagonist, blocked the morphine-induced decrease in PnO GABA levels (n=5 rats). These results show for the first time that ?-opioid receptors in rat PnO modulate GABA levels. A second group of rats (n=6) was used to test the hypothesis that systemically administered morphine also decreases PnO GABA levels. Intravenous morphine caused a significant (p<0.05) decrease (19%) in PnO GABA levels relative to control intravenous infusions of saline. Finally, microinjections followed by 2 h recordings of electroencephalogram and electromyogram tested the hypothesis that PnO morphine administration disrupts sleep (n=8 rats). Morphine significantly (p<0.05) increased the percent of time spent in wakefulness (65%) and significantly (p<0.05) decreased the percent of rapid eye movement (REM) sleep (-53%) and non-REM sleep (-69%). The neurochemical and behavioral data suggest that morphine may disrupt sleep, at least in part, by decreasing GABAergic transmission in the PnO. PMID:17055662

Watson, Christopher J.; Lydic, Ralph; Baghdoyan, Helen A.



Assignment of the human GABA transporter gene (GABATHG) locus to chromosome 3p24-p25  

SciTech Connect

An essential regulatory process of synaptic transmission is the inactivation of released neurotransmitters by the transmitter-specific uptake mechanism, {gamma}-Aminobutyric acid (GABA) is an inhibitory transmitter in the vertebrate central nervous system; its activity is terminated by a high-affinity Na{sup +} and Cl{sup -} -dependent specific GABA transporter (GAT), which carries the neurotransmitter to the presynaptic neuron and/or glial elements surrounding the synaptic cleft. Deficiency of the transporter may cause epilepsy and some other nervous diseases. The human GAT gene (GABATHG), approximately 25 kb in length, has been cloned and sequenced by our colleagues (7). Here the results of the in situ hybridization mapping with the gene are presented. 10 refs., 1 fig.

Huang, Fang; Fei, Jian; Guo, Li-He [Shanghai Institute of Cell Biology, Shanghai (China)] [and others] [Shanghai Institute of Cell Biology, Shanghai (China); and others



Regulation of excitability by extrasynaptic GABA(A) receptors.  


Not only are GABA(A) receptors activated transiently by GABA released at synapses, but high affinity, extrasynaptic GABA(A) receptors are also activated by ambient, extracellular GABA as a more persistent form of signalling (often termed tonic inhibition). Over the last decade tonic GABA(A) receptor-mediated inhibition and the properties of GABA(A) receptors mediating this signalling have received increasing attention. Tonic inhibition is present throughout the central nervous system, but is expressed in a cell-type specific manner (e.g. in interneurons more so than in pyramidal cells in the hippocampus, and in thalamocortical neurons more so than in reticular thalamic neurons in the thalamus). As a consequence, tonic inhibition can have a complex effect on network activity. Tonic inhibition is not fixed but can be modulated by endogenous and exogenous modulators, such as neurosteroids, and by developmental, physiological and pathological regulation of GABA uptake and GABA(A) receptor expression. There is also growing evidence that tonic currents play an important role in epilepsy, sleep (also actions of anaesthetics and sedatives), memory and cognition. Therefore, drugs specifically aimed at targeting the extrasynaptic receptors involved in tonic inhibition could be a novel approach to regulating both physiological and pathological processes. PMID:17671772

Walker, Matthew C; Semyanov, Alexey



Distinctions among GABA A and GABA B responses revealed by calcium channel antagonists, cannabinoids, opioids, and synaptic plasticity in rat hippocampus  

Microsoft Academic Search

Rationale  Hippocampal interneurons release ?-aminobutyric acid (GABA) and produce fast GABAA- and slow GABAB-inhibitory postsynaptic potentials (IPSPs). The regulation of GABAB eIPSPs or the interneurons that produce them are not well understood. In addition, while both ?-opioid receptors (?ORs) and\\u000a cannabinoid CB1R receptors (CB1Rs) are present on hippocampal interneurons, it is not clear how these two systems interact.\\u000a \\u000a \\u000a \\u000a Objectives  This study tests

Carlos A. Lafourcade; Bradley E. Alger



Excitatory Actions of GABA in the Suprachiasmatic Nucleus  

PubMed Central

Neurons in the suprachiasmatic nucleus (SCN) are responsible for the generation of circadian oscillations, and understanding how these neurons communicate to form a functional circuit is a critical issue. The neurotransmitter GABA and its receptors are widely expressed in the SCN where they mediate cell-to-cell communication. Previous studies have raised the possibility that GABA can function as an excitatory transmitter in adult SCN neurons during the day, but this work is controversial. In the present study, we first tested the hypothesis that GABA can evoke excitatory responses during certain phases of the daily cycle by broadly sampling how SCN neurons respond to GABA using extracellular single-unit recording and gramicidin-perforated-patch recording techniques. We found that, although GABA inhibits most SCN neurons, some level of GABA-mediated excitation was present in both dorsal and ventral regions of the SCN, regardless of the time of day. These GABA-evoked excitatory responses were most common during the night in the dorsal SCN region. The Na+-K+-2Cl- cotransporter (NKCC) inhibitor, bumetanide, prevented these excitatory responses. In individual neurons, the application of bumetanide was sufficient to change GABA-evoked excitation to inhibition. Calcium-imaging experiments also indicated that GABA-elicited calcium transients in SCN cells are highly dependent on the NKCC isoform 1 (NKCC1). Finally, Western blot analysis indicated that NKCC1 expression in the dorsal SCN is higher in the night. Together, this work indicates that GABA can play an excitatory role in communication between adult SCN neurons and that this excitation is critically dependent on NKCC1. PMID:18495878

Choi, Hee Joo; Lee, C. Justin; Schroeder, Analyne; Kim, Yoon Sik; Jung, Seung Hoon; Kim, Jeong Sook; Kim, Do Young; Son, Eun Ju; Han, Hee Chul; Hong, Seung Kil; Colwell, Christopher S.; Kim, Yang In



NMDA and carbachol but not AMPA affect differently the release of [3H]GABA in striosome- and matrix-enriched areas of the rat striatum.  


The effects of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA; 10(-3) M), N-methyl-D-aspartate (10(-3) M, in the absence of magnesium or presence of AMPA) and carbachol (10(-3) M) on the release of preloaded [3H]gamma-aminobutyric acid ([3H]GABA) from microdiscs of tissue punched out from sagittal brain slices in striosome- or matrix-enriched areas of the rat striatum have been compared. Although AMPA stimulated similarly the release of [3H]GABA in both striatal compartments, the release of [3H]GABA evoked by either N-methyl-D-aspartate (in the presence of AMPA) or carbachol was more pronounced in matrix- than in striosome-enriched areas. AMPA- and N-methyl-D-aspartate- (in the absence of magnesium) evoked responses were reduced but not abolished in the presence of tetrodotoxin (10(-6) M) in both compartments while the carbachol-evoked release of [3H]GABA was decreased by tetrodotoxin only in the matrix. The interruption of cholinergic transmission by the combined application of atropine (10(-5) M) and pempidine (10(-4) M) was without effect on the AMPA-evoked release of [3H]GABA, but it reduced the N-methyl-D-aspartate- (in the absence of magnesium or presence of AMPA) evoked release of [3H]GABA in both compartments, these reductions being of similar amplitude than those observed with tetrodotoxin. PMID:7525008

Galli, T; Artaud, F; Torrens, Y; Godeheu, G; Desban, M; Glowinski, J; Chéramy, A



Neurosteroids and GABA-A Receptor Function  

PubMed Central

Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals, and the gonads and have potent and selective effects on the GABAA-receptor. 3?-hydroxy A-ring reduced metabolites of progesterone, deoxycorticosterone, and testosterone are positive modulators of GABAA-receptor in a non-genomic manner. Allopregnanolone (3?-OH-5?-pregnan-20-one), 5?-androstane-3?, 17?-diol (Adiol), and 3?5?-tetrahydrodeoxycorticosterone (3?5?-THDOC) enhance the GABA-mediated Cl- currents acting on a site (or sites) distinct from the GABA, benzodiazepine, barbiturate, and picrotoxin binding sites. 3?5?-P and 3?5?-THDOC potentiate synaptic GABAA-receptor function and activate ?-subunit containing extrasynaptic receptors that mediate tonic currents. On the contrary, 3?-OH pregnane steroids and pregnenolone sulfate (PS) are GABAA-receptor antagonists and induce activation-dependent inhibition of the receptor. The activities of neurosteroid are dependent on brain regions and types of neurons. In addition to the slow genomic action of the parent steroids, the non-genomic, and rapid actions of neurosteroids play a significant role in the GABAA-receptor function and shift in mood and memory function. This review describes molecular mechanisms underlying neurosteroid action on the GABAA-receptor, mood changes, and cognitive functions. PMID:22654809

Wang, Mingde



[State of GABA-benzodiazepine receptor complex in diabetic neuropathy: effect of nicotinamide and nicotinoyl-GABA].  


An increase in GABA uptake by isolated rat brain synaptic endings as well as a decrease of pharmacologically active GABA analogue muscimol specific binding have indicated a physiologically drastic failure in realization of GABA-mediated inhibitory effects in CNS induced by diabetic encephalopathy. In spite of the impairment of inhibitory function of GABAergic transmission in diabetes a crucial activation of benzodiazepine receptors was determined, as it is tested by the increase in specific binding of flunitrazepam by synaptic membranes. This increase may play an important role in endogenous control of neural activity associated with the factors undefined so far. Using the approach that GABA, and several synthetic GABA agonists, appear to increase the affinity of the benzodiazepine recognition sites for such ligands, presumably by some allosteric mechanism, the findings concerning the in vitro binding assay technique confirm at least some of the functional characteristics observed between GABA and benzodiazepine receptors in vivo under pathological conditions. Indeed, the absence of activating effect on the affinity of flunitrazepam specific binding in the presence of micromolar concentrations of exogenous GABA implicate diabetes-induced alterations in coupling GABA- and benzodiazepine receptors that might be linked to changes in conformantial state of this membrane-bound complex and could partially explain diabetes-induced impairments of GABAergic transmission evaluated in the present study. Our study suggests that nicotinamide and especially GABA play an important role in improving the functioning of brain GABA-benzodiazepine complex impaired in diabetes through specific ligand-mediated mechanism and can be useful in the management of diabetes-associated brain failures. PMID:14577176

Kuchmerovs'ka, T M; Shymans'ky?, I O; Donchenko, H V; Stepanenko, S P



gamma-Aminobutyric acid stimulates ethylene biosynthesis in sunflower.  

PubMed Central

gamma-Aminobutyric acid (GABA), a nonprotein amino acid, is often accumulated in plants following environmental stimuli that can also cause ethylene production. We have investigated the relationship between GABA and ethylene production in excised sunflower (Helianthus annuus L.) tissues. Exogenous GABA causes up to a 14-fold increase in the ethylene production rate after about 12 h. Cotyledons fed with [14C]GABA did not release substantial amounts of radioactive ethylene despite its chemical similarity to 1-aminocyclopropane-1-carboxylic acid (ACC), indicating that GABA is not likely to be an alternative precursor for ethylene. GABA causes increases in ACC synthase mRNA accumulation, ACC levels, ACC oxidase mRNA levels, and in vitro ACC oxidase activity. In the presence of aminoethoxyvinylglycine or alpha-aminoisobutyric acid, GABA did not stimulate ethylene production. We therefore conclude that GABA stimulates ethylene biosynthesis mainly by promoting ACC synthase transcript abundance. Possible roles of GABA as a signal transducer are suggested. PMID:9306696

Kathiresan, A; Tung, P; Chinnappa, C C; Reid, D M



Immunocytochemical Localization of Amines and GABA in the Optic Lobe of the Butterfly, Papilio xuthus  

PubMed Central

Butterflies have sophisticated color vision. While the spectral organization of the compound eye has been well characterized in the Japanese yellow swallowtail butterfly, Papilio xuthus, neural mechanisms underlying its color vision are largely unexplored. Towards a better understanding of signal processing in the visual system of P. xuthus, we used immunocytochemical techniques to analyze the distribution of transmitter candidates, namely, histamine, serotonin, tyramine and ?-aminobutyric acid (GABA). Photoreceptor terminals in the lamina and medulla exhibited histamine immunoreactivity as demonstrated in other insects. The anti-histamine antiserum also labeled a few large medulla neurons. Medulla intrinsic neurons and centrifugal neurons projecting to the lamina showed serotonin immunoreactivity. Tyramine immunostaining was detected in a subset of large monopolar cells (LMCs) in the lamina, transmedullary neurons projecting to the lobula plate, and cell bodies surrounding the first optic chiasma. An anti-GABA antiserum labeled a subset of LMCs and populations of columnar and tangential neurons surrounding the medulla. Each of the four antisera also labeled a few centrifugal neurons that innervate the lobula complex from the central brain, suggesting that they have neuromodulatory roles. A distinctive feature we found in this study is the possibility that tyramine and GABA act as transmitters in LMCs of P. xuthus, which has not been reported in any other insects so far. PMID:22844431

Hamanaka, Yoshitaka; Kinoshita, Michiyo; Homberg, Uwe; Arikawa, Kentaro



GABA and Glutamate Uptake and Metabolism in Retinal Glial (M?ller) Cells  

PubMed Central

Müller cells, the principal glial cells of the retina, support the synaptic activity by the uptake and metabolization of extracellular neurotransmitters. Müller cells express uptake and exchange systems for various neurotransmitters including glutamate and ?-aminobutyric acid (GABA). Müller cells remove the bulk of extracellular glutamate in the inner retina and contribute to the glutamate clearance around photoreceptor terminals. By the uptake of glutamate, Müller cells are involved in the shaping and termination of the synaptic activity, particularly in the inner retina. Reactive Müller cells are neuroprotective, e.g., by the clearance of excess extracellular glutamate, but may also contribute to neuronal degeneration by a malfunctioning or even reversal of glial glutamate transporters, or by a downregulation of the key enzyme, glutamine synthetase. This review summarizes the present knowledge about the role of Müller cells in the clearance and metabolization of extracellular glutamate and GABA. Some major pathways of GABA and glutamate metabolism in Müller cells are described; these pathways are involved in the glutamate-glutamine cycle of the retina, in the defense against oxidative stress via the production of glutathione, and in the production of substrates for the neuronal energy metabolism. PMID:23616782

Bringmann, Andreas; Grosche, Antje; Pannicke, Thomas; Reichenbach, Andreas



Motor dysfunction in cerebellar Purkinje cell-specific vesicular GABA transporter knockout mice  

PubMed Central

?-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the adult mammalian central nervous system and plays modulatory roles in neural development. The vesicular GABA transporter (VGAT) is an essential molecule for GABAergic neurotransmission due to its role in vesicular GABA release. Cerebellar Purkinje cells (PCs) are GABAergic projection neurons that are indispensable for cerebellar function. To elucidate the significance of VGAT in cerebellar PCs, we generated and characterized PC-specific VGAT knockout (L7-VGAT) mice. VGAT mRNAs and proteins were specifically absent in the 40-week-old L7-VGAT PCs. The morphological characteristics, such as lamination and foliation of the cerebellar cortex, of the L7-VGAT mice were similar to those of the control littermate mice. Moreover, the protein expression levels and patterns of pre- (calbindin and parvalbumin) and postsynaptic (GABA-A receptor ?1 subunit and gephyrin) molecules between the L7-VGAT and control mice were similar in the deep cerebellar nuclei that receive PC projections. However, the L7-VGAT mice performed poorly in the accelerating rotarod test and displayed ataxic gait in the footprint test. The L7-VGAT mice also exhibited severer ataxia as VGAT deficits progressed. These results suggest that VGAT in cerebellar PCs is not essential for the rough maintenance of cerebellar structure, but does play an important role in motor coordination. The L7-VGAT mice are a novel model of ataxia without PC degeneration, and would also be useful for studying the role of PCs in cognition and emotion. PMID:24474904

Kayakabe, Mikiko; Kakizaki, Toshikazu; Kaneko, Ryosuke; Sasaki, Atsushi; Nakazato, Yoichi; Shibasaki, Koji; Ishizaki, Yasuki; Saito, Hiromitsu; Suzuki, Noboru; Furuya, Nobuhiko; Yanagawa, Yuchio



Polycomblike protein PHF1b: a transcriptional sensor for GABA receptor activity  

PubMed Central

Background The ?-aminobutyric acid (GABA) type A receptor (GABAAR) contains the recognition sites for a variety of agents used in the treatment of brain disorders, including anxiety and epilepsy. A better understanding of how receptor expression is regulated in individual neurons may provide novel opportunities for therapeutic intervention. Towards this goal we have studied transcription of a GABAAR subunit gene (GABRB1) whose activity is autologously regulated by GABA via a 10 base pair initiator-like element (?1-INR). Methods By screening a human cDNA brain library with a yeast one-hybrid assay, the Polycomblike (PCL) gene product PHD finger protein transcript b (PHF1b) was identified as a ?1-INR associated protein. Promoter/reporter assays in primary rat cortical cells demonstrate that PHF1b is an activator at GABRB1, and chromatin immunoprecipitation assays reveal that presence of PHF1 at endogenous Gabrb1 is regulated by GABAAR activation. Results PCL is a member of the Polycomb group required for correct spatial expression of homeotic genes in Drosophila. We now show that PHF1b recognition of ?1-INR is dependent on a plant homeodomain, an adjacent helix-loop-helix, and short glycine rich motif. In neurons, it co-immunoprecipitates with SUZ12, a key component of the Polycomb Repressive Complex 2 (PRC2) that regulates a number of important cellular processes, including gene silencing via histone H3 lysine 27 trimethylation (H3K27me3). Conclusions The observation that chronic exposure to GABA reduces PHF1 binding and H3K27 monomethylation, which is associated with transcriptional activation, strongly suggests that PHF1b may be a molecular transducer of GABAAR function and thus GABA-mediated neurotransmission in the central nervous system. PMID:23879974



Immunocytochemical evidence that vigabatrin in rats causes GABA accumulation in glial cells of the retina.  


Vigabatrin (gamma-vinyl-GABA, GVG) is an irreversible inhibitor of GABA-aminotransferase (GABA-T) that is under clinical trial as an antiepileptic drug. Rats were injected (i.p.) with GVG and killed 18 h later. GVG administration reduced retinal GABA-T activity to undetectable levels and increased the GABA content 5-fold. Immunocytochemistry using a GABA antiserum clearly revealed the presence of GABA-IR in the glial Muller cells of retinas from GVG-treated rats but not from controls. This experiment indicates that the administration of drugs which inhibit GABA-T may cause the accumulation of GABA in retinal cells that do not normally possess enough endogenous GABA to be detected by immunocytochemistry. PMID:2710396

Neal, M J; Cunningham, J R; Shah, M A; Yazulla, S



The endogenous GABA bioactivity of camel, bovine, goat and human milks.  


GABA orally administered has several beneficial effects on health, including the regulation of hyperglycaemic states in humans. Those effects are similar to the effects reported for camel milk (CMk); however, it is not known whether compounds with GABAergic activity are present in milk from camels or other species. We determined CMk free-GABA concentration by LS/MS and its bioactivity on human GABA receptors. We found that camel and goat milks have significantly more bioavailable GABA than cow and human milks and are able to activate GABA? receptors. The relationship between GABA and taurine concentrations suggests that whole camel milk may be more efficient to activate GABA?1 receptors than goat milk. Because GABA? receptors are normally found in enteroendocrine cells in the lumen of the digestive tract, these results suggest that GABA in camel and goat milk may participate in GABA-modulated functions of enteroendocrine cells in the GI lumen. PMID:24128504

Limon, Agenor; Gallegos-Perez, Jose-Luis; Reyes-Ruiz, Jorge M; Aljohi, Mohammad A; Alshanqeeti, Ali S; Miledi, Ricardo



Effects of tiagabine in combination with intravenous nicotine in overnight abstinent smokers  

Microsoft Academic Search

Rationale  Preclinical studies suggest that medications enhancing the brain gamma amino butyric acid (GABA) system attenuate the rewarding\\u000a effects of stimulants including nicotine. These preclinical studies have not been followed up in systematic human studies.\\u000a \\u000a \\u000a \\u000a Objectives  This study was conducted to examine the effects of a GABAergic medication, tiagabine, on acute physiological and subjective\\u000a effects of intravenous (i.v.) nicotine and on tobacco

Mehmet Sofuoglu; Maria Mouratidis; Sonah Yoo; Kerry Culligan; Thomas Kosten



Waglerin-1 modulates gamma-aminobutyric acid activated current of murine hypothalamic neurons.  


We examined the effect of Waglerin-1, a peptide of 22 amino acid residues purified from the venom of Wagler's pit viper (Trimeresurus wagleri), on the whole cell current response (I(GABA)) of freshly isolated murine hypothalamic neurons to gamma-aminobutyric acid (GABA). Although the application of 32 microM Waglerin-1 alone had no effect on membrane conductance, coapplication with GABA increased I(GABA) for 78 and suppressed I(GABA) for 44 of the 141 neurons examined. The potentiating effect of Waglerin-1 was associated with a leftward shift of the concentration-response relation of GABA without increasing peak I(GABA). This potentiating effect of Waglerin-1 on I(GABA) mimics diazepam. Furthermore, the benzodiazepine antagonist flumazenil antagonized Waglerin-1 potentiation of I(GABA), These observations suggest that Waglerin-1 acts on the benzodiazepine site of one type of GABA(A) receptor/channel complex to increase its affinity for agonist. In contrast, the depressant effect of Waglerin-1 was associated with a rightward shift of the concentration-response relation of GABA without depressing the maximal I(GABA); this suggests a competitive inhibition of a second class of GABAR. The ability of Waglerin-1 to suppress I(GABA) showed a positive correlation with a similar action of Zn++. As with Zn++, the depressant effect of Waglerin-1 on I(GABA) was more pronounced at negative holding potentials. These observations are discussed in terms of variation in the subunit composition of GABA receptors that murine central nervous system neurons express. PMID:9223541

Ye, J H; McArdle, J J



GABA-induced /sup 36/Cl/sup -/ influx: a biochemical correlate of the physiological event regulated by GABA receptors  

SciTech Connect

Microsacs from whole rat brain were prepared in HEPES-buffered saline, as described by Harris and Allan. GABA-induced /sup 36/Cl/sup -/ influx into brain microsacs at 30/sup 0/C was dose dependent, saturable, and had an ED/sub 50/ of 25 The Hill coefficient of the dose-response curve of the GABA response was >1. Other GABA agonists induced /sup 36/Cl/sup -/ influx similarly and with a rank order that paralleled their physiological potencies. Preincubation with GABA produced receptor desensitization and reduced the influx. Bicuculline inhibited the GABA-induced influx competitively, and the inhibition was stereospecific ((+)bicuculline was >10-fold more effective than (-)bicuculline). The convulsants picrotoxinin and t-butyl-bicyclophosphorothionate also inhibited to GABA-induced /sup 36/Cl/sup -/ influx, but noncompetitively. The same effect was observed with cyclodiene insecticides, and their action was stereospecific. Pentobarbital, on the other hand, potentiated the GABA-induced /sup 36/Cl/sup -/ influx.

Gant, D.; Ramadan, A.; Eldefrawi, A.; Eldefrawi, M.



The Caenorhabditis elegans snf-11 Gene Encodes a Sodium-dependent GABA Transporter Required for Clearance of Synaptic GABA  

PubMed Central

Sodium-dependent neurotransmitter transporters participate in the clearance and/or recycling of neurotransmitters from synaptic clefts. The snf-11 gene in Caenorhabditis elegans encodes a protein of high similarity to mammalian GABA transporters (GATs). We show here that snf-11 encodes a functional GABA transporter; SNF-11–mediated GABA transport is Na+ and Cl? dependent, has an EC50 value of 168 ?M, and is blocked by the GAT1 inhibitor SKF89976A. The SNF-11 protein is expressed in seven GABAergic neurons, several additional neurons in the head and retrovesicular ganglion, and three groups of muscle cells. Therefore, all GABAergic synapses are associated with either presynaptic or postsynaptic (or both) expression of SNF-11. Although a snf-11 null mutation has no obvious effects on GABAergic behaviors, it leads to resistance to inhibitors of acetylcholinesterase. In vivo, a snf-11 null mutation blocks GABA uptake in at least a subset of GABAergic cells; in a cell culture system, all GABA uptake is abolished by the snf-11 mutation. We conclude that GABA transport activity is not essential for normal GABAergic function in C. elegans and that the localization of SNF-11 is consistent with a GABA clearance function rather than recycling. PMID:16641366

Mullen, Gregory P.; Mathews, Eleanor A.; Saxena, Paurush; Fields, Stephen D.; McManus, John R.; Moulder, Gary; Barstead, Robert J.; Quick, Michael W.



Reduced astrocytic contribution to the turnover of glutamate, glutamine, and GABA characterizes the latent phase in the kainate model of temporal lobe epilepsy  

PubMed Central

The occurrence of spontaneous seizures in mesial temporal lobe epilepsy (MTLE) is preceded by a latent phase that provides a time window for identifying and treating patients at risk. However, a reliable biomarker of epileptogenesis has not been established and the underlying processes remain unclear. Growing evidence suggests that astrocytes contribute to an imbalance between excitation and inhibition in epilepsy. Here, astrocytic and neuronal neurotransmitter metabolism was analyzed in the latent phase of the kainate model of MTLE in an attempt to identify epileptogenic processes and potential biomarkers. Fourteen days after status epilepticus, [1-13C]glucose and [1,2-13C]acetate were injected and the hippocampal formation, entorhinal/piriform cortex, and neocortex were analyzed by 1H and 13C magnetic resonance spectroscopy. The 13C enrichment in glutamate, glutamine, and ?-aminobutyric acid (GABA) from [1-13C]glucose was decreased in all areas. Decreased GABA content was specific for the hippocampal formation, together with a pronounced decrease in astrocyte-derived [1,2-13C]GABA and a decreased transfer of glutamine for the synthesis of GABA. Accumulation of branched-chain amino acids combined with decreased [4,5-13C]glutamate in hippocampal formation could signify decreased transamination via branched-chain aminotransferase in astrocytes. The results point to astrocytes as major players in the epileptogenic process, and 13C enrichment of glutamate and GABA as potential biomarkers. PMID:21522161

Alvestad, Silje; Hammer, Janniche; Qu, Hong; Haberg, Asta; Ottersen, Ole Petter; Sonnewald, Ursula



Experiment K-6-18. Study of muscarinic and gaba (benzodiazepine) receptors in the sensory-motor cortex, hippcampus and spinal code  

NASA Technical Reports Server (NTRS)

Frontal lobe samples of rat brains flown aboard Cosmos 1887 were processed for the study of muscarinic (cholinergic) and GABA (benzodiazepine) receptors and for immunocytochemical localization of the neurotransmitter gamma-aminobutyric acid (GABA) and glial fibrillary acidic protein (GFAP). Although radioactive labeling of both muscarinic cholinergic and GABA (benzodiazepine) receptors proved to be successful with the techniques employed, distinct receptor localization of individual laminae of the frontal neocortex was not possible since the sampling of the area was different in the various groups of animals. In spite of efforts made for proper orientation and regional identification of laminae, it was found that a densitometric (quantitation of autoradiograms) analysis of the tissue did not contribute to the final interpretation of the effects of weightlessness on these receptors. As to the immunocytochemical studies the use of both markers, GFAP and GABA antiserum, confirmed the suitability of the techniques for use in frozen material. However, similar problems to those encountered in the receptor studies prevented an adequate interpretation of the effects of micro-G exposure on the localization and distribution of GABA and GFAP. This study did, however, confirm the feasibility of investigating neurotransmitters and their receptors in future space flight experiments.

Daunton, N.; Damelio, F.; Krasnov, I.



Putrescine, a source of gamma-aminobutyric acid in the adrenal gland of the rat.  

PubMed Central

Putrescine is the major source of gamma-aminobutyric acid (GABA) in the rat adrenal gland. Diamine oxidase, and not monoamine oxidase, is essential for GABA formation from putrescine in the adrenal gland. Aminoguanidine, a diamine oxidase inhibitor, decreases the GABA concentration in the adrenal gland by more than 70% after 4 h, and almost to zero in 24 h. Studies using [14C]putrescine confirm that [14C]GABA is the major metabolite of putrescine in the adrenal gland. Inhibition of GABA transaminase by amino-oxyacetic acid does not change the GABA concentration in the adrenal gland, as compared with the brain, where the GABA concentration rises. With aminoguanidine, the turnover time of GABA originating from putrescine in the adrenal gland is 5.6 h, reflecting a slower rate of GABA metabolism compared with the brain. Since GABA in the adrenal gland is almost exclusively derived from putrescine, the role of GABA may relate to the role of putrescine as a growth factor and regulator of cell metabolism. PMID:3135801

Caron, P C; Cote, L J; Kremzner, L T



Depression of extra-cellular GABA and increase of NMDA-induced nitric oxide following acute intra-nuclear administration of alcohol in the cerebellar nuclei of the rat  

Microsoft Academic Search

Gamma-aminobutyric acid (GABA) and nitric oxide are two key-transmitters in cerebellar nuclei, the major output of cerebellar\\u000a circuitry. The aims of this study were to investigate the effects of acute intra-cerebellar administration of ethanol (20\\u000a mM) on extra-cellular levels of GABA and on the NMDA-induced nitric oxide (NO) production using microdialysis in the rat.\\u000a We also studied: (i) the effects

Mario Manto; Massimo Pandolfo



Measurement of GABA-evoked conductance changes of lobster muscle fibres by a three-microelectrode voltage clamp technique.  


The effective membrane conductance and capacity of lobster muscle fibres was measured by a three-intracellular-microelectrode voltage clamp technique. Conductance values agreed well with those determined under current clamp, by means of the 'short' cable equations. Reversible increases in conductance evoked by gamma-aminobutyric acid (GABA) were reflected by differences (delta V) in electrotonic potential amplitude recorded at the centre, and midway between the centre and fibre end respectively. GABA dose--conductance curves derived from cable theory or from delta V measurements were virtually identical. The effective capacity (ceff), determined from the area beneath the 'on' delta V capacity transient, yielded values of the membrane time constant consistently lower than those obtained by the graphical method of E. Stefani & A.B. Steinbach (J. Physiol., London. 203, 383-401 (1969)); one possible explanation for this discrepancy is discussed. In the presence of GABA, the effective capacity was reduced in a dose-related manner. The results were interpreted in terms of an equivalent circuit in which surface membrane was arranged in parallel with cleft-tubular membrane of finite conductance, charged through an access resistance. GABA was though to be decreasing ceff by selectively increasing the conductance of the cleft-tubular membranes. PMID:6127711

Constanti, A; Smart, T G



Neuroprotection of co-activation of GABA receptors by preventing caspase-3 denitrosylation in KA-induced seizures.  


Previous studies have demonstrated that kainic acid (KA)-induced seizures can cause the enhancement of excitation and lead to neuronal death in rat hippocampus. Co-activation of the inhibitory GABA receptors can attenuate the excitatory JNK3 apoptotic signaling pathway via inhibiting the increased assembly of the GluR6-PSD-95-MLK3 signaling module induced by KA in epileptic rat hippocampal CA1 and CA3 regions. Caspase-3 is a cysteine protease located in both the cytoplasm and mitochondrial intermembrane space that is a central effector of many apoptotic pathways. We designed experiments to elucidate the underlying molecular mechanisms of procaspase-3 activation and neuroprotection of co-activation of GABA receptors against neuronal death induced by KA. In this study, we show that co-activation of GABA receptors can attenuate the Fas/FasL apoptotic signaling pathway and inhibit the increased of thioredoxin reductase activity induced by KA, subsequently inhibit the activation of procaspase-3 by diminishing the denitrosylation of its active-site thiol and decreasing the cleavage of the caspase-3 zymogen to its active subunits. These results indicate that co-activation of GABA receptors results in neuroprotection by preventing caspase-3 denitrosylation in KA-induced seizure of rats. PMID:22613773

Wei, Xue-Wen; Yan, Hui; Xu, Bo; Wu, Yong-Ping; Li, Chong; Zhang, Guang-Yi



GABA Metabolism and Transport: Effects on Synaptic Efficacy  

PubMed Central

GABAergic inhibition is an important regulator of excitability in neuronal networks. In addition, inhibitory synaptic signals contribute crucially to the organization of spatiotemporal patterns of network activity, especially during coherent oscillations. In order to maintain stable network states, the release of GABA by interneurons must be plastic in timing and amount. This homeostatic regulation is achieved by several pre- and postsynaptic mechanisms and is triggered by various activity-dependent local signals such as excitatory input or ambient levels of neurotransmitters. Here, we review findings on the availability of GABA for release at presynaptic terminals of interneurons. Presynaptic GABA content seems to be an important determinant of inhibitory efficacy and can be differentially regulated by changing synthesis, transport, and degradation of GABA or related molecules. We will discuss the functional impact of such regulations on neuronal network patterns and, finally, point towards pharmacological approaches targeting these processes. PMID:22530158

Roth, Fabian C.; Draguhn, Andreas



GABA level, gamma oscillation, and working memory performance in schizophrenia.  


A relationship between working memory impairment, disordered neuronal oscillations, and abnormal prefrontal GABA function has been hypothesized in schizophrenia; however, in vivo GABA measurements and gamma band neural synchrony have not yet been compared in schizophrenia. This case-control pilot study (N = 24) compared baseline and working memory task-induced neuronal oscillations acquired with high-density electroencephalograms (EEGs) to GABA levels measured in vivo with magnetic resonance spectroscopy. Working memory performance, baseline GABA level in the left dorsolateral prefrontal cortex (DLPFC), and measures of gamma oscillations from EEGs at baseline and during a working memory task were obtained. A major limitation of this study is a relatively small sample size for several analyses due to the integration of diverse methodologies and participant compliance. Working memory performance was significantly lower for patients than for controls. During the working memory task, patients (n = 7) had significantly lower amplitudes in gamma oscillations than controls (n = 9). However, both at rest and across working memory stages, there were significant correlations between gamma oscillation amplitude and left DLPFC GABA level. Peak gamma frequency during the encoding stage of the working memory task (n = 16) significantly correlated with GABA level and working memory performance. Despite gamma band amplitude deficits in patients across working memory stages, both baseline and working memory-induced gamma oscillations showed strong dependence on baseline GABA levels in patients and controls. These findings suggest a critical role for GABA function in gamma band oscillations, even under conditions of system and cognitive impairments as seen in schizophrenia. PMID:24749063

Chen, Chi-Ming A; Stanford, Arielle D; Mao, Xiangling; Abi-Dargham, Anissa; Shungu, Dikoma C; Lisanby, Sarah H; Schroeder, Charles E; Kegeles, Lawrence S



Regulation of Excitability by Extrasynaptic GABA A Receptors  

Microsoft Academic Search

Not only are GABAA receptors activated transiently by GABA released at synapses,\\u000a but high affinity, extrasynaptic GABAA receptors are also activated by ambient, extracellular\\u000a GABA as a more persistent form of signalling (often termed tonic inhibition). Over the last decade\\u000a tonic GABAA receptor-mediated inhibition and the properties of GABAA\\u000a receptors mediating this signalling have received increasing attention. Tonic inhibition is present

Matthew C. Walker; Alexey Semyanov


Active Dendritic Conductances Dynamically Regulate GABA Release from Thalamic Interneurons  

Microsoft Academic Search

SUMMARY Inhibitory interneurons in thedorsal lateralgeniculate nucleus (dLGN) process visual information by pre- cisely controlling spike timing and by refining the re- ceptive fields of thalamocortical (TC) neurons. Previ- ous studies indicate that dLGN interneurons inhibit TC neurons by releasing GABA from both axons and dendrites. However, the mechanisms controlling GABA release are poorly understood. Here, using si- multaneous whole-cell

Claudio Acuna-Goycolea; Stephan D. Brenowitz; Wade G. Regehr



Antagonistic properties of a natural product – Bicuculline with the gamma-aminobutyric acid receptor: Studied through electrostatic potential mapping, electronic and vibrational spectra using ab initio and density functional theory  

Microsoft Academic Search

(+)-Bicuculline (hereinafter referred to as bicuculline), a phthalide isoquinoline alkaloid is of current interest as an antagonist of gamma-aminobutyric acid (GABA). Its inhibitor properties have been studied through molecular electrostatic potential (MEP) mapping of this molecule and GABA receptor. The hot site on the potential surface of bicuculline, which is also isosteric with GABA receptor, has been used to interpret

Anubha Srivastava; Poonam Tandon; Sudha Jain; B. P. Asthana



Regulation of neuronal and recombinant GABA(A) receptor ion channels by xenovulene A, a natural product isolated from Acremonium strictum.  


Xenovulene A (XR368) is a natural product exhibiting little structural resemblance with classical benzodiazepines yet is able to displace high-affinity ligand binding to the benzodiazepine site of the gamma-aminobutyric acid (GABA)A receptor. We have characterized this compound and an associated congener (XR7009) by use of radioligand binding and electrophysiological methodologies with native neurons and the Xenopus oocyte expression system. Xenovulene A, and the more potent XR7009, inhibited [3H]flunitrazepam binding to rat forebrain with Ki values of 7 and 192 nM, and 1.7 and 42 nM, respectively, each site accounting for approximately 50% of the total specific binding. In cerebellar and spinal cord membranes, these ligands identified only single binding sites. These ligands demonstrated no intrinsic agonist activity at recombinant GABA(A) receptors comprising alpha1beta1gamma2S subunits expressed in Xenopus oocytes, yet at 1 microM both significantly potentiated the GABA-induced response and reduced the GABA EC50 from 10.9 (control) to 5.1 (Xenovulene A) or 2.7 microM (XR7009). The rank potency order for enhancement of the 10 microM GABA response is: XR7009 (EC50, 0.02 microM) > diazepam (0.03) > Xenovulene A (0.05) > flurazepam (0.17). The activity of XR368 and XR7009 was reduced by the benzodiazepine antagonist, flumazenil, and absent in receptors devoid of the gamma2 subunit. These agents exhibited receptor subtype selectivity because alpha3beta1gamma2S receptors were less sensitive to these compounds relative to alpha1 subunit-containing receptors, whereas alpha6beta1gamma2S receptors were completely insensitive. Potentiation of the response to GABA on native GABA(A) receptors in cortical neurons substantiates the profile of the novel structures of Xenovulene A and XR7009 as specific benzodiazepine agonists. PMID:9262310

Thomas, P; Sundaram, H; Krishek, B J; Chazot, P; Xie, X; Bevan, P; Brocchini, S J; Latham, C J; Charlton, P; Moore, M; Lewis, S J; Thornton, D M; Stephenson, F A; Smart, T G



Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines.  


GABA(A) receptors are pentameric ligand-gated ion channels involved in fast inhibitory neurotransmission and are allosterically modulated by the anxiolytic, anticonvulsant, and sedative-hypnotic benzodiazepines. Here we show that the prokaryotic homolog ELIC also is activated by GABA and is modulated by benzodiazepines with effects comparable to those at GABA(A) receptors. Crystal structures reveal important features of GABA recognition and indicate that benzodiazepines, depending on their concentration, occupy two possible sites in ELIC. An intrasubunit site is adjacent to the GABA-recognition site but faces the channel vestibule. A second intersubunit site partially overlaps with the GABA site and likely corresponds to a low-affinity benzodiazepine-binding site in GABA(A) receptors that mediates inhibitory effects of the benzodiazepine flurazepam. Our study offers a structural view how GABA and benzodiazepines are recognized at a GABA-activated ion channel. PMID:23035248

Spurny, Radovan; Ramerstorfer, Joachim; Price, Kerry; Brams, Marijke; Ernst, Margot; Nury, Hugues; Verheij, Mark; Legrand, Pierre; Bertrand, Daniel; Bertrand, Sonia; Dougherty, Dennis A; de Esch, Iwan J P; Corringer, Pierre-Jean; Sieghart, Werner; Lummis, Sarah C R; Ulens, Chris



Loss of zolpidem efficacy in the hippocampus of mice with the GABA A receptor ?2 F77I point mutation  

Microsoft Academic Search

Zolpidem is a hypnotic benzodiazepine site agonist with some c-aminobutyric acid (GABA)A receptor subtype selectivity. Here, we have tested the effects of zolpidem on the hippocampus of c2 subunit (c2F77I) point mutant mice. Analysis of forebrain GABAA receptor expression with immunocytochemistry, quantitative (3H)muscimol and (35S) t-butylbicyclophosphorothionate (TBPS) autoradiography, membrane binding with (3H)flunitrazepam and (3H)muscimol, and comparison of miniature inhibitory postsynaptic

D. W. Cope; C. Halbsguth; T. Karayannis; P. Wulff; F. Ferraguti; H. Hoeger; E. Leppä; A.-M. Linden; A. Oberto; W. Ogris; E. R. Korpi; W. Sieghart; P. Somogyi; W. Wisden; M. Capogna



Quantum Dot Conjugates of GABA and Muscimol: Binding to ?1?2?2 and ?1 GABAA Receptors  

PubMed Central

GABAA receptors are ligand-gated ion channels that mediate inhibitory synaptic signaling in the CNS. Fluorescent probes with the ability to target these receptors can provide insights into receptor location, distribution and dynamics in live cells, while revealing abnormalities in their distribution and dynamics that could occur in a variety of diseases. We have developed fluorescent probes of GABAA receptors that are composed of a CdSe/ZnS core–shell nanocrystal (quantum dot; qdot) conjugated to pegylated derivatives of the GABA receptor agonists GABA and muscimol (GABA-qdots and muscimol-qdots, respectively). Quantitative fluorescence imaging was used to analyze the binding activity of these conjugates to ?1?2?2 GABAA and ?1 GABAA receptors expressed in Xenopus oocytes. The selectivity of these conjugates for ?1?2?2 GABAA and ?1 GABAA receptors was determined by their ability to compete with the antagonists bicuculline and methyl-(1,2,3,6-tetrahydropyridin-4-yl)phosphinic acid (TPMPA). Both GABA- and muscimol-qdots exhibited robust binding to both ?1?2?2 and ?1 GABAA receptors. At ?1?2?2 receptors, pretreatment with bicuculline reduced conjugate binding by ?8-fold on average, an extent far exceeding the reduction produced by TPMPA (?30%). Conversely, at ?1 receptors, pretreatment with TPMPA inhibited binding by ?10-fold, an extent greatly exceeding the change produced by bicuculline (?50% or less). These results indicate specific binding of muscimol-qdots and GABA-qdots to ?1?2?2 GABAA and ?1 GABAA receptors in a manner that preserves the respective pharmacological sensitivities of these receptors to TPMPA and bicuculline, and encourage the use of qdot-conjugated neurotransmitter analogs as labeling agents at GABAA receptors. PMID:23509979



Evidence for reduced tonic levels of GABA in the hippocampus of an animal model of ADHD, the spontaneously hypertensive rat.  


Recent studies have investigated the role of ?-aminobutyric acid (GABA) in the behavioural symptoms of attention-deficit/hyperactivity disorder (ADHD), specifically in behavioural disinhibition. Spontaneously hypertensive rats (SHR) are widely accepted as an animal model of ADHD, displaying core symptoms of the disorder. Using an in vitro superfusion technique, we have shown that glutamate-stimulated release of radio-actively labelled norepinephrine ([(3)H]NE) from prefrontal cortex and hippocampal slices is greater in SHR than in their normotensive control strain, Wistar-Kyoto rats (WKY), and/or a standard control strain, Sprague-Dawley rats (SD). In the present study, we investigated how the level of extracellular (tonic) GABA affects release of [(3)H]NE in hippocampal slices of male and female SHR, WKY and SD rats, in response to 3 glutamate stimulations (S1, S2, and S3). The hippocampal slices were prelabelled with [(3)H]NE and superfused with buffer containing 0?M, 1?M, 10?M, or 100?M GABA. Three consecutive glutamate stimulations were achieved by exposing slices to 3 pulses of glutamate (1mM), each separated by 10min. Increasing tonic levels of GABA increased basal and stimulated release of [(3)H]NE in all strains. When GABA was omitted from the superfusion buffer used to perfuse SHR hippocampal slices, but present at 100µM in the buffer used to perfuse WKY and SD hippocampal slices, glutamate-stimulated release of [(3)H]NE was similar in all three strains. In these conditions, the decrease in [(3)H]NE release from S1 to S2 and S3 was also similar in all three strains. These findings suggest that extracellular concentrations of GABA may be reduced in SHR hippocampus, in vivo, compared to WKY and SD. An underlying defect in GABA function may be at the root of the dysfunction in catecholamine transmission noted in SHR, and may underlie their ADHD-like behaviours. PMID:24161405

Sterley, Toni-Lee; Howells, Fleur M; Russell, Vivienne A



Depolarizing actions of ?-aminobutyric acid and related compounds on rat superior cervical ganglia in vitro  

PubMed Central

1 Potential changes in rat superior cervical ganglia were recorded in vitro with surface electrodes. 2 ?-aminobutyric acid (GABA) produced a transient, low-amplitude ganglion depolarization at rest, and a transient hyperpolarization in ganglia depolarized by carbachol. Depolarization was not prevented by preganglionic denervation. The log dose-response curve for depolarization was sigmoid with a mean ED50 of 12.5 ?M. 3 The ganglion was depolarized in similar manner by the following compounds (mean molar potencies relative to GABA (=1) in brackets): 3-aminopropane sulphonic acid (3.4), ?-amino-?-hydroxybutyric acid (0.27), ?-guanidino-propionic acid (0.12), guanidinoacetic acid (0.057), ?-aminovaleric acid (0.048), ?-alanine (0.01), 2,4-diaminobutyric acid, ?-guanidinobutyric acid, taurine and N-methyl-GABA (all <0.01). The following compounds did not depolarize the ganglion at 10 mM concentrations: ?- and ?-amino-n-butyric acids, ?-amino-iso-butyric acid, glycine and glutamic acid. 4 Depolarization declined in the continued presence of GABA. Ganglia thus `desensitized' to GABA showed a diminished response to other amino acids but not to carbachol. 5 The effect of GABA was not antagonized by hyoscine and hexamethonium in combination, in concentrations sufficient to block responses to carbachol. 6 Responses to GABA were blocked more readily than those to carbachol by bicuculline (IC50, 14 ?M) and picrotoxin (IC50, 37 ?M). Strychnine (IC50, 73 ?M) was a relatively weak and less selective GABA-antagonist. 7 It is concluded that sympathetic ganglion cells possess receptors for GABA and related amino acids which are (a) different from the acetylcholine receptors and (b) similar to GABA receptors in the central nervous system. PMID:4154116

Bowery, N.G.; Brown, D.A.



Cerebral radioprotection by pentobarbital: Dose-response characteristics and association with GABA agonist activity  

SciTech Connect

Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose, a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose. Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time.

Olson, J.J.; Friedman, R.; Orr, K.; Delaney, T.; Oldfield, E.H. (National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (USA))



GABA receptors, alcohol dependence and criminal behavior.  


The aim of this study was to analyze the connection between alcohol dependence and criminal behavior by an integrated genetic-environmental approach. The research, structured as a case-control study, examined 186 alcohol-dependent males; group 1 (N = 47 convicted subjects) was compared with group 2 (N = 139 no previous criminal records). Genetic results were innovative, highlighting differences in genotype distribution (p = 0.0067) in group 1 for single-nucleotide polymorphism rs 3780428, located in the intronic region of subunit 2 of the GABA B receptor gene (GABBR2). Some environmental factors (e.g., grade repetition) were associated with criminal behavior; others (e.g., attendance at Alcoholics Anonymous) were inversely related to convictions. The concomitant presence of the genetic and environmental factors found to be associated with the condition of alcohol-dependent inmate showed a 4-fold increase in the risk of antisocial behavior. The results need to be replicated on a larger population to develop new preventive and therapeutic proposals. PMID:23822588

Terranova, Claudio; Tucci, Marianna; Sartore, Daniela; Cavarzeran, Fabiano; Di Pietra, Laura; Barzon, Luisa; Palù, Giorgio; Ferrara, Santo D



Molecular pharmacology of an insect GABA receptor  

E-print Network

Abbreviations 3-APP 3-aminopropylphosphonic acid 4-AB 4-amino-1-butanol 5-AV 5-aminopentanoic acid 5-HT 5-hydroxy-tryptamine aa Amino acid Å angstrom (1×10?10 M) ACh Acetylcholine AChBP Acetylcholine binding protein APS Ammonium persulfate...

McGonigle, Ian Vincent



Suppression of Progesterone-enhanced Hyperactivation in Hamster Spermatozoa by ?-aminobutyric Acid  

PubMed Central

It has been recently shown that mammalian spermatozoa were hyperactivated by steroids, amines and amino acids. In the present study, we investigated whether hyperactivation of hamster sperm is regulated by progesterone (P) and ?-aminobutyric acid (GABA). Although sperm hyperactivation was enhanced by P, GABA significantly suppressed P-enhanced hyperactivation in a dose-dependent manner. Suppression of P-enhanced hyperactivation by GABA was significantly inhibited by an antagonist of the GABAA receptor (bicuculline). Moreover, P bound to the sperm head, and this binding was decreased by GABA. Because the concentrations of GABA and P change in association with the estrous cycle, these results suggest that GABA and P competitively regulate the enhancement of hyperactivation through the GABAA receptor. PMID:24614320

KON, Hiroe; TAKEI, Gen L.; FUJINOKI, Masakatsu; SHINODA, Motoo



Differential effects of GABAB receptor subtypes, {gamma}-hydroxybutyric Acid, and Baclofen on EEG activity and sleep regulation.  


The role of GABA(B) receptors in sleep is still poorly understood. GHB (?-hydroxybutyric acid) targets these receptors and is the only drug approved to treat the sleep disorder narcolepsy. GABA(B) receptors are obligate dimers comprised of the GABA(B2) subunit and either one of the two GABA(B1) subunit isoforms, GABA(B1a) and GABA(B1b). To better understand the role of GABA(B) receptors in sleep regulation, we performed electroencephalogram (EEG) recordings in mice devoid of functional GABA(B) receptors (1(-/-) and 2(-/-)) or lacking one of the subunit 1 isoforms (1a(-/-) and 1b(-/-)). The distribution of sleep over the day was profoundly altered in 1(-/-) and 2(-/-) mice, suggesting a role for GABA(B) receptors in the circadian organization of sleep. Several other sleep and EEG phenotypes pointed to a more prominent role for GABA(B1a) compared with the GABA(B1b) isoform. Moreover, we found that GABA(B1a) protects against the spontaneous seizure activity observed in 1(-/-) and 2(-/-) mice. We also evaluated the effects of the GHB-prodrug GBL (?-butyrolactone) and of baclofen (BAC), a high-affinity GABA(B) receptor agonist. Both drugs induced a state distinct from physiological sleep that was not observed in 1(-/-) and 2(-/-) mice. Subsequent sleep was not affected by GBL whereas BAC was followed by a delayed hypersomnia even in 1(-/-) and 2(-/-) mice. The differential effects of GBL and BAC might be attributed to differences in GABA(B)-receptor affinity. These results also indicate that all GBL effects are mediated through GABA(B) receptors, although these receptors do not seem to be involved in mediating the BAC-induced hypersomnia. PMID:20962240

Vienne, Julie; Bettler, Bernhard; Franken, Paul; Tafti, Mehdi



Influence of light on the free amino acid content and ?-aminobutyric acid synthesis in Brassica juncea seedlings.  


Glutamate decarboxylase (GAD; EC is an important enzyme in ?-aminobutyric acid (GABA) biosynthesis. Here we report the influence of light on amino acid accumulation and investigate the molecular mechanism by which light influences GABA biosynthesis at the seedling stage of two mustard (Brassica juncea) cultivars (green-leaf and purple-leaf). Gene expression profiles of four GAD-encoding genes (GAD1, GAD2, GAD4a, and GAD4b) and their impact on GABA biosynthesis were analyzed. Light exerted an obvious influence on amino acid accumulation in mustard seedlings. GAD gene expression was also significantly regulated by light/dark or dark treatment, which differentially regulated GABA biosynthesis in B. juncea seedlings. High-performance liquid chromatography (HPLC) revealed that the seeds of purple cultivars contain a higher amount of free amino acids and GABA than do the seeds of green cultivars. After seed germination, however, the accumulation of free amino acids peaked in dark-treated seedlings on day 9 in both cultivars, whereas GABA synthesis peaked at 9 days under light conditions. This study may provide a foundation for understanding the effect of light on amino acids, particularly GABA biosynthesis in Brassica plants. PMID:23909820

Li, Xiaohua; Kim, Yeon Bok; Uddin, Md Romij; Lee, Sanghyun; Kim, Sun-Ju; Park, Sang Un



Drosophila neuroligin 4 regulates sleep through modulating GABA transmission.  


Sleep is an essential and evolutionarily conserved behavior that is closely related to synaptic function. However, whether neuroligins (Nlgs), which are cell adhesion molecules involved in synapse formation and synaptic transmission, are involved in sleep is not clear. Here, we show that Drosophila Nlg4 (DNlg4) is highly expressed in large ventral lateral clock neurons (l-LNvs) and that l-LNv-derived DNlg4 is essential for sleep regulation. GABA transmission is impaired in mutant l-LNv, and sleep defects in dnlg4 mutant flies can be rescued by genetic manipulation of GABA transmission. Furthermore, dnlg4 mutant flies exhibit a severe reduction in GABAA receptor RDL clustering, and DNlg4 associates with RDLs in vivo. These results demonstrate that DNlg4 regulates sleep through modulating GABA transmission in l-LNvs, which provides the first known link between a synaptic adhesion molecule and sleep in Drosophila. PMID:24068821

Li, Yi; Zhou, Zikai; Zhang, Xinwang; Tong, Huawei; Li, Peipei; Zhang, Zi Chao; Jia, Zhengping; Xie, Wei; Han, Junhai



GABA-B receptor activation and conflict behavior  

SciTech Connect

Baclofen and oxazepam enhance extinction of conflict behavior in the Geller-Seifter test while baclofen and diazepam release punished behavior in Vogel's conflict test. In order to investigate the possibility that the effect of the selective GABA-B receptor agonist baclofen is mediated indirectly via the GABA-A/benzodiazepine receptor complex, the effect of pretreatment of rats with baclofen on (/sup 3/H)-diazepam binding to washed and unwashed cortical and cerebellar membranes of rats has been studied. Baclofen pretreatment increase Bmax in washed cerebellar membranes when bicuculline was present in the incubation mixture. No effect was seen in cortical membranes. The present results render it unlikely that the effect of baclofen on extinction of conflict behavior and punished drinking is mediated via the GABA-A/benzodiazepine receptor complex. 50 references, 1 figure, 4 tables.

Ketelaars, C.E.J.; Bollen, E.L.; Rigter, H.; Bruinvels, J.



Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene.  


The gamma-aminobutyric acid type-A (GABA(A)) receptor plays a major role in inhibitory neurotransmissions. Intronic SNPs and haplotypes in GABRB2, the gene for GABA(A) receptor beta(2) subunit, are associated with schizophrenia and correlated with the expression of two alternatively spliced beta(2) isoforms. In the present study, using chimpanzee as an ancestral reference, high frequencies were observed for the derived (D) alleles of the four SNPs rs6556547, rs187269, rs1816071 and rs1816072 in GABRB2, suggesting the occurrence of positive selection for these derived alleles. Coalescence-based simulation showed that the population frequency spectra and the frequencies of H56, the haplotype having all four D alleles, significantly deviated from neutral-evolution expectation in various demographic models. Haplotypes containing the derived allele of rs1816072 displayed significantly less diversity compared to haplotypes containing its ancestral allele, further supporting positive selection. The variations in DD-genotype frequencies in five human populations provided a snapshot of the evolutionary history, which suggested that the positive selections of the D alleles are recent and likely ongoing. The divergence between the DD-genotype profiles of schizophrenic and control samples pointed to the schizophrenia-relevance of positive selections, with the schizophrenic samples showing weakened selections compared to the controls. These DD-genotypes were previously found to increase the expression of beta(2), especially its long isoform. Electrophysiological analysis showed that this long beta(2) isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABA(A) receptor function by energy depletion. These findings represent the first demonstration of positive selection in a schizophrenia-associated gene. PMID:17520021

Lo, Wing-Sze; Xu, Zhiwen; Yu, Zhiliang; Pun, Frank W; Ng, Siu-Kin; Chen, Jianhuan; Tong, Ka-Lok; Zhao, Cunyou; Xu, Xiaojing; Tsang, Shui-Ying; Harano, Mutsuo; Stöber, Gerald; Nimgaonkar, Vishwajit L; Xue, Hong



Estriol affects prolactin and LH secretion in rats.  


The effects of estriol on serum prolactin (PRL) and LH levels, on the pituitary response to TRH and LHRH and on the synthesis and release of PRL from the anterior pituitary gland were investigated in female rats. The increase of serum PRL levels after estradiol administration was found to be associated with an increase of glutamic acid decarboxylase (GAD) and GABA-transaminase (GABA-T) in the hypothalamus. Thus, a study was carried out on the effects of estradiol and estriol on PRL secretion and on GAD, GABA-T and gamma-amino butyric acid (GABA) in the hypothalamus and the anterior pituitary. Under basal and TRH-stimulated conditions, estriol increased serum PRL levels, decreased basal serum LH levels, and increased the response to LHRH, in terms of LH release. Estradiol and estriol increased the synthesis and release of 3H-PRL from hemipituitary glands in incubations of pretreated animals. Both estrogens induced hyperprolactinemia, concomitantly with an increase of hypothalamic GAD and GABA-T activity. Estriol increased hypothalamic GABA concentration, but did not modify GABA concentration in the pituitary glands. Our results show that estriol, at relatively high doses, seems to be active in increasing PRL synthesis and release and in decreasing serum LH levels; it can also modify pituitary response to TRH and LHRH stimulation. PMID:2501380

Diaz, M C; Seilicovich, A; Duvilanski, B H; Siseles, N; Lasaga, M; Debeljuk, L



Quercetin antagonism of GABAA?? receptors is prevented by ascorbic acid through a redox-independent mechanism.  


Quercetin is a natural flavonoid widely distributed in plants that acts as a neuroprotective agent and modulates the activity of different synaptic receptors and ion channels, including the ionotropic GABA receptors. GABA(A??) receptors were shown to be antagonized by quercetin, but the mechanisms underlying these antagonistic actions are still unknown. We have analyzed here if the antagonistic action produced by quercetin on GABA(A??) receptors was related to its redox activity or due to alternative mechanism/s. Homomeric GABA(A??) receptors were expressed in frog oocytes and GABA-evoked responses electrophysiologically recorded. Quercetin effects on GABA(A??) receptors were examined in the absence or presence of ascorbic acid. Chemical protection of cysteines by selective sulfhydryl reagents and site directed mutagenesis experiments were also used to determine ?? subunit residues involved in quercetin actions. Quercetin antagonized GABA(A??) receptor responses in a dose-dependent, fast and reversible manner. Quercetin inhibition was prevented in the presence of ascorbic acid, but not by thiol reagents that modify the extracellular Cys-loop of these receptors. H141, an aminoacidic residue located near to the ?? subunit GABA binding site, was involved in the allosteric modulation of GABA(A??) receptors by several agents including ascorbic acid. Quercetin similarly antagonized GABA-evoked responses mediated by mutant (H141D)GABA(A??) and wild-type receptors, but prevention exerted by ascorbic acid on quercetin effects was impaired in mutant receptors. Taken together the present results suggest that quercetin antagonistic actions on GABA(A??) receptors are mediated through a redox-independent allosteric mechanism. PMID:23916728

Calero, Cecilia I; Beltrán González, Andrea N; Gasulla, Javier; Alvarez, Silvia; Evelson, Pablo; Calvo, Daniel J



GABA-receptor complex in monkeys treated with MPTP  

SciTech Connect

Tissue samples from the brains of monkeys made parkinsonian by the depletion of dopamine (DA) with dopaminergic neurotoxin (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1.4-3.4 mg/kg, i.v.) were assayed for changed in GABA ((/sup 3/H)-GABA), benzodiazepine ((/sup 3/H)-flunitrazepam) and picrotoxin ((/sup 35/S)-TBPS) binding sites. One point binding assays were performed on globus pallidus (GP), substantia nigra reticulata (SN/sub R/) and VA-VL thalamic samples. GABA binding was markedly increased in the SN/sub R/ (129 +/- 12%, n = 2) and GP (108 +/- 33%, n = 4) and not altered in the striatum or thalamus. However, benzodiazepine binding was increased in the striatum (170%; 257 fm/mg, control; 692 fm/mg, treated) and GP (28%; 317 fm/mg, control, 405 fm/mg, treated) and (/sup 35/S)-TBPS binding was also increased in GP (100%; 32.5 fm/mg, control; 65.5 fm/mg, treated). atScatchard analysis of (/sup 3/H)-GABA binding was also performed on tissue samples of motor cortex, cerebellar vermis and striatum pooled from half brains of 4 parkinsonian and 2 control monkeys. Depletion of DA (92 +/- 5%) in the striatum of these monkeys was not associated with any change in the K/sub D/ or B/sub max/ for the high or low affinity GABA binding sites in the striatum, motor cortex or cerebellum. Thus, in the basal ganglia, DA depletion is associated with an increase in GABA binding sites in GP and SN/sub R/, an increase in picrotoxin binding sites in GP and an increase in benzodiazepine binding sites in the striatum.

Huffman, R.D.; Ticku, M.K.



Modulation of GABA-A receptors of astrocytes and STC-1 cells by taurine structural analogs.  


Taurine activates and modulates GABA receptors in vivo as well as those expressed in heterologous systems. This study aimed to determine whether the structural analogs of taurine: homotaurine and hypotaurine, have the ability to activate GABA-A receptors that include GABA? subunits. The expression of GABA-A receptors containing GABA? has been reported in the STC-1 cells and astrocytes. In both cell types, taurine, homo-, and hypotaurine gated with low efficiency a picrotoxin-sensitive GABA-A receptor. The known bimodal modulatory effect of taurine on GABA? receptors was not observed; however, differences between the activation and deactivation rates were detected when they were perfused together with GABA. In silico docking simulations suggested that taurine, hypo-, and homotaurine do not form a cation-? interaction such as that generated by GABA in the agonist-binding site of GABA?. This observation complements the electrophysiological data suggesting that taurine and its analogs act as partial agonists of GABA-A receptors. All the observations above suggest that the structural analogs of taurine are partial agonists of GABA-A receptors that occupy the agonist-binding site, but their structures do not allow the proper interaction with the receptor to fully gate its Cl(-) channel. PMID:25119985

Reyes-Haro, Daniel; Cabrera-Ruíz, Elizabeth; Estrada-Mondragón, Argel; Miledi, Ricardo; Martínez-Torres, Ataúlfo



Distinct types of ionic modulation of GABA actions in pyramidal cells and interneurons during electrical  

E-print Network

the slow depolarization in GABA- and glutamate-dependent fashion, leading to the initiation of seizure that is always preceded by GABA-dependent slow depolarization. These afterdischarge responses are synchronous. The extents of slow depolarization and GABA conversion were much larger in the pyramidal cell group than

Fukai, Tomoki


Development/Plasticity/Repair A Noncanonical Release of GABA and Glutamate Modulates  

E-print Network

Development/Plasticity/Repair A Noncanonical Release of GABA and Glutamate Modulates Neuronal Immature neurons express GABA and glutamate receptors before synapse formation, and both transmitters mechanisms. We conclude that GABA and, to a lesser degree, glutamate released in a SNARE

Paris-Sud XI, Université de


Contribution of a glial glutamate transporter to GABA synthesis in the retina  

E-print Network

Contribution of a glial glutamate transporter to GABA synthesis in the retina Vijay P. Sarthy transportershavebeen shown to play a rolein GABA synthesis by enhancing glutamate uptake. In the present study, we have examined whether a glial glutamate transporter, GLAST, has a role in GABA synthesis in the mammalian retina

Marc, Robert E.


Activation of neurokinin-1 receptors promotes GABA release at synapses in the rat entorhinal cortex  

Microsoft Academic Search

We have previously shown that activation of neurokinin-1 receptors reduces acutely provoked epileptiform activity in rat entorhinal cortex in vitro, and suggested that this may result from an increase in GABA release from inhibitory interneurones. In the present study we have made whole cell patch clamp recordings of spontaneous GABA-mediated inhibitory postsynaptic currents as an indicator of GABA release in

A. E. Stacey; G. L. Woodhall; R. S. G. Jones



A Novel GABA Receptor on Bipolar Cell Terminals in the Tiger Salamander Retina  

Microsoft Academic Search

We studied the pharmacology of the GABA receptors on bipolar cell terminals in the retinal slice preparation. Whole- cell patch-clamp recordings were made from the somas of bipolar cells and GABA was puffed near their terminals, after synaptic transmission was blocked. GABA puffs evoked a large chloride current that was reduced by picrotoxin, but in many cells this current was

Peter D. Lukasiewicz; Bruce R. Maple; Frank S. Werbh



The metabotropic glutamate receptor 7 (mGluR7) allosteric agonist AMN082 modulates nucleus accumbens GABA and glutamate, but not dopamine, in rats.  


The group III metabotropic glutamate receptor 7 (mGluR7) has been implicated in many neurological and psychiatric diseases, including drug addiction. However, it is unclear whether and how mGluR7 modulates nucleus accumbens (NAc) dopamine (DA), L-glutamate or gamma-aminobutyric acid (GABA), important neurotransmitters believed to be involved in such neuropsychiatric diseases. In the present study, we found that systemic or intra-NAc administration of the mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082) dose-dependently lowered NAc extracellular GABA and increased extracellular glutamate, but had no effect on extracellular DA levels. Such effects were blocked by (R,S)-alpha-methylserine-O-phosphate (MSOP), a group III mGluR antagonist. Intra-NAc perfusion of tetrodotoxin (TTX) blocked the AMN082-induced increases in glutamate, but failed to block the AMN082-induced reduction in GABA, suggesting vesicular glutamate and non-vesicular GABA origins for these effects. In addition, blockade of NAc GABAB receptors by 2-hydroxy-saclofen itself elevated NAc extracellular glutamate. Intra-NAc perfusion of 2-hydroxy-saclofen not only abolished the enhanced extracellular glutamate normally produced by AMN082, but also decreased extracellular glutamate in a TTX-resistant manner. We interpret these findings to suggest that the increase in glutamate is secondary to the decrease in GABA, which overcomes mGluR7 activation-induced inhibition of non-vesicular glutamate release. In contrast to its modulatory effect on GABA and glutamate, the mGluR7 receptor does not appear to modulate NAc DA release. PMID:18155073

Li, Xia; Gardner, Eliot L; Xi, Zheng-Xiong



The Metabotropic Glutamate Receptor 7 (mGluR7) Allosteric Agonist AMN082 Modulates Nucleus Accumbens GABA and Glutamate, but not Dopamine, in Rats  

PubMed Central

The group III metabotropic glutamate receptor 7 (mGluR7) has been implicated in many neurological and psychiatric diseases, including drug addiction. However, it is unclear whether and how mGluR7 modulates nucleus accumbens (NAc) dopamine (DA), l-glutamate or ?-aminobutyric acid (GABA), important neurotransmitters believed to be involved in such neuropsychiatric diseases. In the present study, we found that systemic or intra-NAc administration of the mGluR7 allosteric agonist N,N’-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082) dose-dependently lowered NAc extracellular GABA and increased extracellular glutamate, but had no effect on extracellular DA levels. Such effects were blocked by (R,S)-?-methylserine-O-phosphate (MSOP), a group III mGluR antagonist. Intra-NAc perfusion of tetrodotoxin (TTX) blocked the AMN082-induced increases in glutamate, but failed to block the AMN082-induced reduction in GABA, suggesting vesicular glutamate and non-vesicular GABA origins for these effects. In addition, blockade of NAc GABAB receptors by 2-hydroxy-saclofen itself elevated NAc extracellular glutamate. Intra-NAc perfusion of 2-hydroxy-saclofen not only abolished the enhanced extracellular glutamate normally produced by AMN082, but also decreased extracellular glutamate in a TTX-resistant manner. We interpret these findings to suggest that the increase in glutamate is secondary to the decrease in GABA, which overcomes mGluR7 activation-induced inhibition of non-vesicular glutamate release. In contrast to its modulatory effect on GABA and glutamate, the mGluR7 receptor does not appear to modulate NAc DA release. PMID:18155073

Li, Xia; Gardner, Eliot L.; Xi, Zheng-Xiong



Influence of GABA-gated bicarbonate conductance on potential, current and intracellular chloride in crayfish muscle fibres.  

PubMed Central

1. The effects of gamma-aminobutyric acid (GABA) on membrane potential and conductance as well as on the intracellular Cl- activity (aiCl) and intracellular pH (pHi) were studied in crayfish muscle fibres using a three-microelectrode voltage clamp and ion-selective microelectrodes. In the presence of CO2-HCO3-, the intracellular HCO3- activity (aiHCO3) was estimated from pHi. 2. In a nominally HCO3(-)-free solution, a near-saturating concentration of GABA (0.2 mM) produced a marked increase in membrane conductance but little change in potential. In a solution containing 30 mM-HCO3- (equilibrated with 5% CO2 + 95% air; pH 7.4), the GABA-induced increase in conductance was associated with a depolarization of about 15 mV, with an increase in aiCl and with a decrease in aiHCO3. All these effects were blocked by picrotoxin (PTX). The depolarizing action of GABA was augmented following depletion of extracellular and intracellular Cl-. 3. The GABA-induced increase in aiCl which took place in the presence of HCO3- was blocked by clamping the membrane potential at its resting level. This indicates that the increase in aiCl was due to passive redistribution of Cl-. In both the presence and absence of HCO3-, the GABA-activated transmembrane flux of Cl- showed reversal at the level of the resting potential, which indicates that under steady-state conditions the Cl- equilibrium potential (ECl) is identical to the resting potential. 4. In a Cl(-)-free, 30 mM-HCO3(-)-containing solution, 0.5 mM-GABA produced a PTX-sensitive increase in conductance which amounted to 15% of the conductance activated in the presence of Cl-. In the absence of both Cl- and HCO3-, the respective figure was 2.8%. Assuming constant-field conditions, the conductance data yielded a permeability ratio PHCO3/PCl of 0.42 for the GABA-activated channels. 5. In a Cl(-)-containing, HCO3(-)-free solution, the reversal potential of the GABA-activated current (EGABA) was, by about 1 mV, less negative than the resting membrane potential (RP). In a solution containing Cl- and 30 mM-HCO3-, EGABA-RP was 12 mV. Simultaneous measurements of EGABA, aiCl and aiHCO3 (pHi) gave a PHCO3/PCl value of 0.33. 6. In a Cl(-)-free, HCO3(-)-containing solution EGABA was close to the HCO3- equilibrium potential (EHCO3) and an experimental acidosis which produced a negative shift in EHCO3 was associated with a similar shift in EGABA.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2481729

Kaila, K; Pasternack, M; Saarikoski, J; Voipio, J



P2X2 and P2X4 receptor expression is regulated by a GABA(A) receptor-mediated mechanism in the gerbil hippocampus.  


Fast responses to extracellular ATP are mediated by the activation of P2X receptors. Native and cloned P2X receptors are permeable to monovalent cations such as Na+ and K+ as well as divalent cations such as Ca2+. However, altered P2X receptor expression has not been definitively determined under pathological conditions, particularly in epilepsy. Here we show that, in the seizure-sensitive (SS) gerbil hippocampus, a recognized genetic epilepsy model, the expressions of both P2X2 and P2X4 receptors are markedly decreased as compared with that in the seizure-resistant (SR) gerbil. These alterations are closely related to changes in gamma-aminobutyric acid (GABA) concentrations induced by vigabatrin (VGB) or 3-mercaptopropionic acid (3-MPA) treatment. Furthermore, the regulation of both P2X receptor expression in the gerbil hippocampus was mediated by the GABA(A) receptor, not GABA(B). These results suggest that the GABA(A) receptor-mediated modulation of P2X receptor expression may play an important role in the regulation of neuronal excitability. PMID:12941474

Kang, Tae-Cheon; An, Sung-Jin; Park, Seung-Kook; Hwang, In-Koo; Won, Moo Ho



The Role of Genetic Sex in Affect Regulation and Expression of GABA-Related Genes Across Species.  


Although circulating hormones and inhibitory gamma-aminobutyric acid (GABA)-related factors are known to affect mood, considerable knowledge gaps persist for biological mechanisms underlying the female bias in mood disorders. Here, we combine human and mouse studies to investigate sexual dimorphism in the GABA system in the context of major depressive disorder (MDD) and then use a genetic model to dissect the role of sex-related factors in GABA-related gene expression and anxiety-/depressive-like behaviors in mice. First, using meta-analysis of gene array data in human postmortem brain (N?=?51 MDD subjects, 50 controls), we show that the previously reported down-regulation in MDD of somatostatin (SST), a marker of a GABA neuron subtype, is significantly greater in women with MDD. Second, using gene co-expression network analysis in control human subjects (N?=?214; two frontal cortex regions) and expression quantitative trait loci mapping (N?=?170 subjects), we show that expression of SST and the GABA-synthesizing enzymes glutamate decarboxylase 67 (GAD67) and GAD65 are tightly co-regulated and influenced by X-chromosome genetic polymorphisms. Third, using a rodent genetic model [Four Core Genotypes (FCG) mice], in which genetic and gonadal sex are artificially dissociated (N???12/group), we show that genetic sex (i.e., X/Y-chromosome) influences both gene expression (lower Sst, Gad67, Gad65 in XY mice) and anxiety-like behaviors (higher in XY mice). This suggests that in an intact male animal, the observed behavior represents the outcomes of male genetic sex increasing and male-like testosterone decreasing anxiety-like behaviors. Gonadal sex was the only factor influencing depressive-like behavior (gonadal males?GABA-related genes and anxiety-like behaviors. PMID:24062698

Seney, Marianne L; Chang, Lun-Ching; Oh, Hyunjung; Wang, Xingbin; Tseng, George C; Lewis, David A; Sibille, Etienne



Systematic review of gamma-aminobutyric-acid inhibitory deficits across the reproductive life cycle.  


Deficiencies in the inhibitory functioning of gamma-aminobutyric acid (GABA) have been implicated in the pathophysiology of depressive disorders. Reproductive life cycle events, including menstruation, pregnancy, and menopause, are consistently associated with increased psychopathology, in particular mood disorders. Given that GABA-inhibitory activity may be modulated directly or indirectly by estrogen, progesterone, and their metabolites receptors, it has been hypothesized that GABA deficits may be evident during these reproductive periods. We aimed to compare GABA function among women during these "high-risk" reproductive periods to GABA function among women at other time periods. We conducted a systematic review of studies comparing women during reproductive life stages associated with depressive disorder risk (luteal phase of the menstrual cycle, perinatal period, and menopausal transition) to women at other time periods. The study outcome was GABA function. The review included 11 studies, 9 focused on the menstrual cycle, and 2 focused on the perinatal period. GABA-inhibitory function fluctuated across the menstrual cycle, with differing patterns in women with and without depressive disorders. GABA-inhibitory function was reduced in pregnancy and early postpartum compared to the nonpregnant state. Key limitations were the absence of studies evaluating the menopausal transition, and the heterogeneity of GABA outcome measures. GABA-inhibitory function fluctuates across the menstrual cycle and is reduced perinatally. This has potential implications for a role of GABAergically mediated interventions in the prevention and treatment of menstrual cycle-related and perinatal depressive disorders. PMID:24420415

Vigod, Simone N; Strasburg, Kate; Daskalakis, Zafiris J; Blumberger, Daniel M



Trial of Zolpidem, Eszopiclone, and Other GABA Agonists in a Patient with Progressive Supranuclear Palsy  

PubMed Central

Progressive supranuclear palsy (PSP) is a progressive, debilitating neurodegenerative disease of the Parkinson-plus family of syndromes. Unfortunately, there are no pharmacologic treatments for this condition, as most sufferers of the classic variant respond poorly to Parkinson medications such as levodopa. Zolpidem, a gamma aminobutyric acid (GABA) agonist specific to the ?-1 receptor subtype, has been reported to show improvements in symptoms of PSP patients, including motor dysfunction, dysarthria, and ocular disturbances. We observed a 73-year-old woman with a six-year history of PSP, who, upon administration of a single 12.5?mg dose of sustained-release zolpidem, exhibited marked enhancements in speech, facial expressions, and fine motor skills for five hours. These results were reproduced upon subsequent clinic visits. In an effort to find a sustainable medication that maximized these beneficial effects while minimizing side effects and addressing some of her comorbid neuropsychological conditions, a trial of five other GABA receptor agonists was performed with the patient's consent, while she and her caregivers were blinded to the specific medications. She and her caretakers subsequently reported improvements, especially visual, while on eszopiclone, and, to a lesser degree, temazepam and flurazepam. PMID:25371679

Chang, Andrew Young; Weirich, Erica



Trial of Zolpidem, Eszopiclone, and Other GABA Agonists in a Patient with Progressive Supranuclear Palsy.  


Progressive supranuclear palsy (PSP) is a progressive, debilitating neurodegenerative disease of the Parkinson-plus family of syndromes. Unfortunately, there are no pharmacologic treatments for this condition, as most sufferers of the classic variant respond poorly to Parkinson medications such as levodopa. Zolpidem, a gamma aminobutyric acid (GABA) agonist specific to the ?-1 receptor subtype, has been reported to show improvements in symptoms of PSP patients, including motor dysfunction, dysarthria, and ocular disturbances. We observed a 73-year-old woman with a six-year history of PSP, who, upon administration of a single 12.5?mg dose of sustained-release zolpidem, exhibited marked enhancements in speech, facial expressions, and fine motor skills for five hours. These results were reproduced upon subsequent clinic visits. In an effort to find a sustainable medication that maximized these beneficial effects while minimizing side effects and addressing some of her comorbid neuropsychological conditions, a trial of five other GABA receptor agonists was performed with the patient's consent, while she and her caregivers were blinded to the specific medications. She and her caretakers subsequently reported improvements, especially visual, while on eszopiclone, and, to a lesser degree, temazepam and flurazepam. PMID:25371679

Chang, Andrew Young; Weirich, Erica



Ventral tegmental area GABA neurons and opiate motivation  

PubMed Central

Rational Past research has demonstrated that when an animal changes from a previously drug-naive to an opiate-dependent and withdrawn state, morphine’s motivational effects are switched from a tegmental pedunculopontine nucleus (TPP)-dependent to a dopamine-dependent pathway. Interestingly, a corresponding change is observed in ventral tegmental area (VTA) GABAA receptors, which change from mediating hyperpolarization of VTA GABA neurons to mediating depolarization. Objectives The present study investigated whether pharmacological manipulation of VTA GABAA receptor activity could directly influence the mechanisms underlying opiate motivation. Results Using an unbiased place conditioning procedure, we demonstrated that in Wistar rats, intra-VTA administration of furosemide, a Cl? cotransporter inhibitor, was able to promote a switch in the mechanisms underlying morphine’s motivational properties, one which is normally observed only after chronic opiate exposure. This behavioral switch was prevented by intra-VTA administration of acetazolamide, an inhibitor of the bicarbonate ion-producing carbonic anhydrase enzyme. Electrophysiological recordings of mouse VTA showed that furosemide reduced the sensitivity of VTA GABA neurons to inhibition by the GABAA receptor agonist muscimol, instead increasing the firing rate of a significant subset of these GABA neurons. Conclusion Our results suggest that the carbonic anhydrase enzyme may constitute part of a common VTA GABA neuron-based biological pathway responsible for controlling the mechanisms underlying opiate motivation, supporting the hypothesis that VTA GABAA receptor hyperpolarization or depolarization is responsible for selecting TPP- or dopamine-dependent motivational outputs, respectively. PMID:23392354

Vargas-Perez, Hector; Mabey, Jennifer K.; Shin, Samuel I.; Steffensen, Scott C.; van der Kooy, Derek



GABA Transporter-1 Deficiency Confers Schizophrenia-Like Behavioral Phenotypes  

PubMed Central

The mechanism underlying the pathogenesis of schizophrenia remains poorly understood. The hyper-dopamine and hypo-NMDA receptor hypotheses have been the most enduring ideas. Recently, emerging evidence implicates alterations of the major inhibitory system, GABAergic neurotransmission in the schizophrenic patients. However, the pathophysiological role of GABAergic system in schizophrenia still remains dubious. In this study, we took advantage of GABA transporter 1 (GAT1) knockout (KO) mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related behavioral abnormalities. We found that GAT1 KO mice displayed multiple behavioral abnormalities related to schizophrenic positive, negative and cognitive symptoms. Moreover, GAT1 deficiency did not change the striatal dopamine levels, but significantly enhanced the tonic GABA currents in prefrontal cortex. The GABAA receptor antagonist picrotoxin could effectively ameliorate several behavioral defects of GAT1 KO mice. These results identified a novel function of GAT1, and indicated that the elevated ambient GABA contributed critically to the pathogenesis of schizophrenia. Furthermore, several commonly used antipsychotic drugs were effective in treating the locomotor hyperactivity in GAT1 KO mice, suggesting the utility of GAT1 KO mice as an alternative animal model for studying schizophrenia pathogenesis and developing new antipsychotic drugs. PMID:23922840

Yu, Zhe; Fang, Qi; Xiao, Xian; Wang, Yi-Zhi; Cai, You-Qing; Cao, Hui; Hu, Gang; Chen, Zhong; Fei, Jian; Gong, Neng; Xu, Tian-Le



Spectral editing of weakly coupled spins using variable flip angles in PRESS constant echo time difference spectroscopy: Application to GABA  

NASA Astrophysics Data System (ADS)

A general in vivo magnetic resonance spectroscopy editing technique is presented to detect weakly coupled spin systems through subtraction, while preserving singlets through addition, and is applied to the specific brain metabolite ?-aminobutyric acid (GABA) at 4.7 T. The new method uses double spin echo localization (PRESS) and is based on a constant echo time difference spectroscopy approach employing subtraction of two asymmetric echo timings, which is normally only applicable to strongly coupled spin systems. By utilizing flip angle reduction of one of the two refocusing pulses in the PRESS sequence, we demonstrate that this difference method may be extended to weakly coupled systems, thereby providing a very simple yet effective editing process. The difference method is first illustrated analytically using a simple two spin weakly coupled spin system. The technique was then demonstrated for the 3.01 ppm resonance of GABA, which is obscured by the strong singlet peak of creatine in vivo. Full numerical simulations, as well as phantom and in vivo experiments were performed. The difference method used two asymmetric PRESS timings with a constant total echo time of 131 ms and a reduced 120° final pulse, providing 25% GABA yield upon subtraction compared to two short echo standard PRESS experiments. Phantom and in vivo results from human brain demonstrate efficacy of this method in agreement with numerical simulations.

Snyder, Jeff; Hanstock, Chris C.; Wilman, Alan H.



Anticonvulsant effects of the wasp Polybia ignobilis venom on chemically induced seizures and action on GABA and glutamate receptors.  


Venoms of spiders and wasps are well recognized to present high affinity to the central nervous tissue of many mammalian species. Here we describe the effects of direct exposure of rat (Rattus norvegicus) brains to the crude and denatured venom of the Brazilian social wasp Polybia ignobilis. Lower doses of crude venom injected via intracerebroventricular (i.c.v.) inhibited the exploratory activity of animals, while higher doses provoked severe generalized tonic-clonic seizures, with hind limb extension. The status epilepticus lasted for few minutes leading the animals to respiratory depression and death. In contrast, the denatured venom was anticonvulsant against acute seizures induced by the i.c.v. injection of bicuculline, picrotoxin and kainic acid, but it was ineffective against seizures caused by systemic pentylenetetrazole. Moreover, the [3H]-glutamate binding in membranes from rat brain cortex was inhibited by the denatured venom in lower concentrations than the [3H]-GABA binding. The denatured venom contains free GABA and glutamate (34 and 802 pg/microg of venom, respectively), but they are not the major binding inhibitors. These interactions of venom components with GABA and glutamate receptors could be responsible for the anticonvulsant effects introducing the venom from P. ignobilis as a potential pharmacological source of anticonvulsant drugs. PMID:15953769

Cunha, Alexandra Olimpio Siqueira; Mortari, Márcia Renata; Oliveira, Luciana; Carolino, Ruither Oliveira Gomes; Coutinho-Netto, Joaquim; dos Santos, Wagner Ferreira



Different transporter systems regulate extracellular GABA from vesicular and non-vesicular sources  

PubMed Central

Tonic GABA type A (GABAA) conductance is a key factor regulating neuronal excitability and computation in neuronal networks. The magnitude of the tonic GABAA conductance depends on the concentration of ambient GABA originating from vesicular and non-vesicular sources and is tightly regulated by GABA uptake. Here we show that the transport system regulating ambient GABA responsible for tonic GABAA conductances in hippocampal CA1 interneurons depends on its source. In mice, GABA from vesicular sources is regulated by mouse GABA transporter 1 (mGAT1), while that from non-vesicular sources by mouse GABA transporters 3/4 (mGAT3/4). This finding suggests that the two transporter systems do not just provide backup for each other, but regulate distinct signaling pathways. This allows individual tuning of the two signaling systems and indicates that drugs designed to act at specific transporters will have distinct therapeutic actions. PMID:23494150

Song, Inseon; Volynski, Kirill; Brenner, Tanja; Ushkaryov, Yuri; Walker, Matthew; Semyanov, Alexey



Inhibition of recombinant N-type and native high voltage-gated neuronal Ca{sup 2+} channels by AdGABA: Mechanism of action studies  

SciTech Connect

High-voltage activated Ca{sup 2+} (Ca{sub V}) channels play a key role in the regulation of numerous physiological events by causing transient changes in the intracellular Ca{sup 2+} concentration. These channels consist of a pore-forming Ca{sub V}{alpha}{sub 1} protein and three auxiliary subunits (Ca{sub V}{beta}, Ca{sub V}{alpha}{sub 2}{delta} and Ca{sub V}{gamma}). Ca{sub V}{alpha}{sub 2}{delta} is an important component of Ca{sub V} channels in many tissues and of great interest as a drug target. It is well known that anticonvulsant agent gabapentin (GBP) binds to Ca{sub V}{alpha}{sub 2}{delta} and reduces Ca{sup 2+} currents by modulating the expression and/or function of the Ca{sub V}{alpha}{sub 1} subunit. Recently, we showed that an adamantane derivative of GABA, AdGABA, has also inhibitory effects on Ca{sub V} channels. However, the importance of the interaction of AdGABA with the Ca{sub V}{alpha}{sub 2}{delta} subunit has not been conclusively demonstrated and the mechanism of action of the drug has yet to be elucidated. Here, we describe studies on the mechanism of action of AdGABA. Using a combined approach of patch-clamp recordings and molecular biology we show that AdGABA inhibits Ca{sup 2+} currents acting on Ca{sub V}{alpha}{sub 2}{delta} only when applied chronically, both in a heterologous expression system and in dorsal root-ganglion neurons. AdGABA seems to require uptake and be acting intracellularly given that its effects are prevented by an inhibitor of the L-amino acid transport system. Interestingly, a mutation in the Ca{sub V}{alpha}{sub 2}{delta} that abolishes GBP binding did not affect AdGABA actions, revealing that its mechanism of action is similar but not identical to that of GBP. These results indicate that AdGABA is an important Ca{sub V}{alpha}{sub 2}{delta} ligand that regulates Ca{sub V} channels.

Martinez-Hernandez, Elizabeth [Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies of the National Polytechnic Institute (Cinvestav-IPN), Mexico City (Mexico); Sandoval, Alejandro [School of Medicine FES Iztacala, National Autonomous University of Mexico (UNAM), Tlalnepantla (Mexico); Gonzalez-Ramirez, Ricardo [Department of Molecular Biology and Histocompatibility 'Dr. Manuel Gea Gonzalez' General Hospital, Ministry of Health, Mexico City (Mexico); Zoidis, Grigoris [Department of Pharmaceutical Chemistry, University of Athens (Greece); Felix, Ricardo, E-mail: [Department of Cell Biology, Cinvestav-IPN (Mexico)



Glutamate, GABA, and Other Cortical Metabolite Concentrations during Early Abstinence from Alcohol and their Associations with Neurocognitive Changes*  

PubMed Central

BACKGROUND Little is known about the effects of alcohol dependence on cortical concentrations of glutamate (Glu) or gamma aminobutyric acid (GABA). We used proton magnetic resonance spectroscopy (MRS) to study cross-sectionally and longitudinally the concentrations of these Glu and GABA in alcohol dependent individuals (ALC) during early abstinence from alcohol. Methods Twenty ALC were studied at about one week of abstinence from alcohol (baseline) and 36 ALC at five weeks of abstinence and compared to 16 light/non-drinking controls (LD). Eleven ALC were studied twice during abstinence. Participants underwent clinical interviewing, blood work, neuropsychological testing, structural imaging and single-volume proton MRS at 4 Tesla. Absolute concentrations of Glu, GABA and those of other 1H MRS-detectable metabolites were measured in the anterior cingulate (ACC), parieto-occipital cortex (POC) and dorso-lateral prefrontal cortex (DLPFC). Relationships of metabolite levels to drinking severity and neurocognition were also assessed. Results ALC at baseline had lower concentrations of Glu, N-acetylaspartate (NAA), and choline- (Cho) and creatine-containing metabolites than LD in the ACC, but normal GABA and myo-inositol (mI) levels. At five weeks of abstinence, metabolite concentrations were not significantly different between groups. Between one and five weeks of abstinence, Glu, NAA and Cho levels in the ACC increased significantly. Higher cortical mI concentrations in ALC related to worse neurocognitive outcome. Conclusion These MRS data suggest compromised and regionally specific bioenergetics/metabolism in one-week-abstinent ALC that largely normalizes over four weeks of sustained abstinence. The correlation between mI levels and neurocognition affirms the functional relevance of this putative astrocyte marker. PMID:22503310

Mon, Anderson; Durazzo, Timothy C.; Meyerhoff, Dieter J.



Evidence for a dual effect of gamma-aminobutyric acid on thyrotropin (TSH)-releasing hormone-induced TSH release from perifused rat pituitaries.  


The effects of gamma-aminobutyric acid (GABA) on the spontaneous and TRH-induced TSH release were investigated in vitro on perifused rat pituitaries. The dynamic pattern of TSH release was measured in response to a 6-min pulse of TRH (10 nM) with or without GABA addition. GABA had no effect on spontaneous TSH release but exhibited a dual effect on TSH-stimulated release according to the dose (as calculated by the induced-basal ratio): a potentiation of the TSH response to TRH at the lowest concentrations tested (less than or equal to 10 nM) and an inhibition for GABA concentrations equal or higher than 100 nM. The GABA potentiation was mimicked by muscimol (10 microM) and isoguvacine (10 nM) but not by baclofen (1 microM). Bicucullin (1 microM) or picrotoxin (1 microM) added 15 min before GABA was unable to reverse the GABA potentiation of the TSH response, although SR 95103 (1 and 10 microM), a specific GABA A antagonist, partially or totally antagonized this response. Diazepam (7 nM) was able to potentiate the TSH response by 216% when GABA was added to the system at a concentration (60 nM) which does not modify by itself the TSH response. The inhibitory effect of GABA (100 nM) was completely abolished by bicucullin (1 microM), by picrotoxin (1 microM), and by SR 95103 (1 microM). Picrotoxin not only blocked the inhibitory action of GABA but significantly (P less than 0.05) potentiated the TSH response to TRH. Our data suggest a dual GABA-ergic control of TRH-stimulated TSH release directly on the pituitary, probably mediated by two different kinds of GABA receptors: a GABA A receptor site mediating the inhibitory effect and a nonclassical GABA A receptor site of higher affinity for its stimulatory action. PMID:3113920

Tapia-Arancibia, L; Roussel, J P; Astier, H



Caenorhabditis elegans Neuromuscular Junction: GABA Receptors and Ivermectin Action  

PubMed Central

The prevalence of human and animal helminth infections remains staggeringly high, thus urging the need for concerted efforts towards this area of research. GABA receptors, encoded by the unc-49 gene, mediate body muscle inhibition in Caenorhabditis elegans and parasitic nematodes and are targets of anthelmintic drugs. Thus, the characterization of nematode GABA receptors provides a foundation for rational anti-parasitic drug design. We therefore explored UNC-49 channels from C. elegans muscle cultured cells of the first larval stage at the electrophysiological and behavioral levels. Whole-cell recordings reveal that GABA, muscimol and the anthelmintic piperazine elicit macroscopic currents from UNC-49 receptors that decay in their sustained presence, indicating full desensitization. Single-channel recordings show that all drugs elicit openings of ?2.5 pA (+100 mV), which appear either as brief isolated events or in short bursts. The comparison of the lowest concentration required for detectable channel opening, the frequency of openings and the amplitude of macroscopic currents suggest that piperazine is the least efficacious of the three drugs. Macroscopic and single-channel GABA-activated currents are profoundly and apparently irreversibly inhibited by ivermectin. To gain further insight into ivermectin action at C. elegans muscle, we analyzed its effect on single-channel activity of the levamisol-sensitive nicotinic receptor (L-AChR), the excitatory receptor involved in neuromuscular transmission. Ivermectin produces a profound inhibition of the frequency of channel opening without significant changes in channel properties. By revealing that ivermectin inhibits C. elegans muscle GABA and L-AChR receptors, our study adds two receptors to the already known ivermectin targets, thus contributing to the elucidation of its pleiotropic effects. Behavioral assays in worms show that ivermectin potentiates piperazine-induced paralysis, thus suggesting that their combination is a good strategy to overcome the increasing resistance of parasites, an issue of global concern for human and animal health. PMID:24743647

Hernando, Guillermina; Bouzat, Cecilia



Canadian boreal pulp and paper feedstocks contain neuroactive substances that interact in vitro with GABA and dopaminergic systems in the brain.  


Pulp and paper wood feedstocks have been previously implicated as a source of chemicals with the ability to interact with or disrupt key neuroendocrine endpoints important in the control of reproduction. We tested nine Canadian conifers commonly used in pulp and paper production as well as 16 phytochemicals that have been observed in various pulp and paper mill effluent streams for their ability to interact in vitro with the enzymes monoamine oxidase (MAO), glutamic acid decarboxylase (GAD), and GABA-transaminase (GABA-T), and bind to the benzodiazepine-binding site of the GABA(A) receptor (GABA(A)-BZD). These neuroendocrine endpoints are also important targets for treatment of neurological disorders such as anxiety, epilepsy, or depression. MAO and GAD were inhibited by various conifer extracts of different polarities, including major feedstocks such as balsam fir, black spruce, and white spruce. MAO was selectively stimulated or inhibited by many of the tested phytochemicals, with inhibition observed by a group of phenylpropenes (e.g. isoeugenol and vanillin). Selective GAD inhibition was also observed, with all of the resin acids tested being inhibitory. GABA(A)-BZD ligand displacement was also observed. We compiled a table identifying which of these phytochemicals have been described in each of the species tested here. Given the diversity of conifer species and plant chemicals with these specific neuroactivities, it is reasonable to propose that MAO and GAD inhibition reported in effluents is phytochemical in origin. We propose disruption of these neuroendocrine endpoints as a possible mechanism of reproductive inhibition, and also identify an avenue for potential research and sourcing of conifer-derived neuroactive natural products. PMID:24041600

Waye, Andrew; Annal, Malar; Tang, Andrew; Picard, Gabriel; Harnois, Frédéric; Guerrero-Analco, José A; Saleem, Ammar; Hewitt, L Mark; Milestone, Craig B; MacLatchy, Deborah L; Trudeau, Vance L; Arnason, John T



NMDA-mediated release of glutamate and GABA in the subthalamic nucleus is mediated by dopamine: an in vivo microdialysis study in rats.  


The present study investigated the effects of N-methyl-D-aspartic acid.H2O (NMDA) on the dopamine, glutamate and GABA release in the subthalamic nucleus (STN) by using in vivo microdialysis in rats. NMDA (100 micromol/L) perfused through the microdialysis probe evoked an increase in extracellular dopamine in the STN of the intact rat of about 170%. This coincided with significant increases in both extracellular glutamate (350%) and GABA (250%). The effect of NMDA perfusion on neurotransmitter release at the level of the STN was completely abolished by co-perfusion of the selective NMDA-receptor antagonist MK-801 (10 micromol/L), whereas subthalamic perfusion of MK-801 alone had no effect on extracellular neurotransmitter concentrations. Furthermore, NMDA induced increases in glutamate were abolished by both SCH23390 (8 micromol/L), a selective D1 antagonist, and remoxipride (4 micromol/L), a selective D2 antagonist. The NMDA induced increase in GABA was abolished by remoxipride but not by SCH23390. Perfusion of the STN with SCH23390 or remoxipride alone had no effect on extracellular neurotransmitter concentrations. The observed effects in intact animals depend on the nigral dopaminergic innervation, as dopamine denervation, by means of 6-hydroxydopamine lesioning of the substantia nigra, clearly abolished the effects of NMDA on neurotransmitter release at the level of the STN. Our work points to a complex interaction between dopamine, glutamate and GABA with a crucial role for dopamine at the level of the STN. PMID:17727638

Ampe, Ben; Massie, Ann; D'Haens, Jean; Ebinger, Guy; Michotte, Yvette; Sarre, Sophie



GABA receptors inhibited by benzodiazepines mediate fast inhibitory transmission in the central amygdala.  


The amygdala is intimately involved in emotional behavior, and its role in the generation of anxiety and conditioned fear is well known. Benzodiazepines, which are commonly used for the relief of anxiety, are thought to act by enhancing the action of the inhibitory transmitter GABA. We have examined the properties of GABA-mediated inhibition in the amygdala. Whole-cell recordings were made from neurons in the lateral division of the central amygdala. Application of GABA evoked a current that reversed at the chloride equilibrium potential. Application of the GABA antagonists bicuculline or SR95531 inhibited the GABA-evoked current in a manner consistent with two binding sites. Stimulation of afferents to neurons in the central amygdala evoked an IPSC that was mediated by the release of GABA. The GABA(A) receptor antagonists bicuculline and picrotoxin failed to completely block the IPSC. The bicuculline-resistant IPSC was chloride-selective and was unaffected by GABA(B)-receptor antagonists. Furthermore, this current was insensitive to modulation by general anesthetics or barbiturates. In contrast to their actions at GABA(A) receptors, diazepam and flurazepam inhibited the bicuculline-resistant IPSC in a concentration-dependent manner. These effects were fully antagonized by the benzodiazepine site antagonist Ro15-1788. We conclude that a new type of ionotropic GABA receptor mediates fast inhibitory transmission in the central amygdala. This receptor may be a potential target for the development of new therapeutic strategies for anxiety disorders. PMID:10559379

Delaney, A J; Sah, P



Coupling Sap Flow Velocity and Amino Acid Concentrations as an Alternative Method to 15N Labeling for Quantifying Nitrogen Remobilization by Walnut Trees1  

PubMed Central

The temporal dynamics of N remobilization was studied in walnut (Juglans nigra × regia) trees growing in sand culture. Trees were fed with labeled N (15N) during 1999 and unlabeled N in 2000. Total N and 15N contents in different tree compartments were measured during 80 d after bud burst and were used to estimate N remobilization for spring growth. The seasonal (and occasionally diurnal) dynamics of the concentration and 15N enrichment of the major amino acids in xylem sap were determined concurrently. Sap flow velocity was also measured for sample trees. A new approach coupling amino acid concentrations to sap flow velocity for quantifying N remobilization was tested. A decrease of the labeled N contents of medium roots, tap roots, and trunk was observed concurrently to the increase in the labeled N content of new shoots. Remobilized N represented from previous year storage 54% of N recovered in new shoots. Arginine, citruline, ?-amino butyric acid, glutamic acid, and aspartic acid always represented around 80% of total amino acid and amide N in xylem sap and exhibited specific seasonal trends and significant diurnal trends. N translocation was mainly insured by arginine during the first 15 d after bud burst, and then by glutamic acid and citruline. The pattern of N remobilization estimated by the new approach was consistent with that measured by the classical labeling technique. Implications for quantifying N remobilization for large, field-growing trees are discussed. PMID:12376667

Frak, Ela; Millard, Peter; Le Roux, Xavier; Guillaumie, Sabine; Wendler, Renate



Glutamate, GABA and Acetylcholine Signaling Components in the Lamina of the Drosophila Visual System  

PubMed Central

Synaptic connections of neurons in the Drosophila lamina, the most peripheral synaptic region of the visual system, have been comprehensively described. Although the lamina has been used extensively as a model for the development and plasticity of synaptic connections, the neurotransmitters in these circuits are still poorly known. Thus, to unravel possible neurotransmitter circuits in the lamina of Drosophila we combined Gal4 driven green fluorescent protein in specific lamina neurons with antisera to ?-aminobutyric acid (GABA), glutamic acid decarboxylase, a GABAB type of receptor, L-glutamate, a vesicular glutamate transporter (vGluT), ionotropic and metabotropic glutamate receptors, choline acetyltransferase and a vesicular acetylcholine transporter. We suggest that acetylcholine may be used as a neurotransmitter in both L4 monopolar neurons and a previously unreported type of wide-field tangential neuron (Cha-Tan). GABA is the likely transmitter of centrifugal neurons C2 and C3 and GABAB receptor immunoreactivity is seen on these neurons as well as the Cha-Tan neurons. Based on an rdl-Gal4 line, the ionotropic GABAA receptor subunit RDL may be expressed by L4 neurons and a type of tangential neuron (rdl-Tan). Strong vGluT immunoreactivity was detected in ?-processes of amacrine neurons and possibly in the large monopolar neurons L1 and L2. These neurons also express glutamate-like immunoreactivity. However, antisera to ionotropic and metabotropic glutamate receptors did not produce distinct immunosignals in the lamina. In summary, this paper describes novel features of two distinct types of tangential neurons in the Drosophila lamina and assigns putative neurotransmitters and some receptors to a few identified neuron types. PMID:18464935

Kolodziejczyk, Agata; Sun, Xuejun; Meinertzhagen, Ian A.; Nassel, Dick R.



The investigation of structural and thermosensitive properties of new phosphazene derivatives bearing glycol and amino acid.  


In this study, hexachlorocyclotriphosphazene, N(3)P(3)Cl(6) (cylotriphosphazene), was reacted with hydrophilic and hydrophobic groups to synthesize amphiphilic phosphazene derivatives (4-12). Cylotriphosphazene was reacted triethylene glycol monomethyl ether (TEGME), dipropylene glycol monomethyl ether (DPGME), diethylene glycol monobutyl ether (DEGBE), (1 : 3 mole proportion) in the presence of sodium hydride and using tetrahydrofuran (THF) as solvent at -60 °C. Three isomers (nongeminal cis-2,4,6 (1a-3a); nongeminal trans-2,4,6 (1b-3b); geminal 2,2,4 (1c-3c)) were isolated from the reaction of hexachlorocyclotriphosphazatriene (trimer) (1) with TEGME, DPGME and DEGBE. The substitution reactions of cis-tris isomers (1a-3a) with 4-amino butyric acid, 5-amino valeric acid and 6-amino hexanoic acid were separately done to provide amphiphilic phosphazenes (4-12). All compounds were characterized by using elemental analysis, (31)P NMR and mass spectroscopy. Thermosensitive properties of compounds were studied. The compounds (4-12) were soluble in both water and organic media that shows they are amphiphilic molecules. Concentration-dependent LCST (Lower Critical Solution Temperature) behaviours of new compounds (4-12) were measured in water. Compounds 7, 9, 11 and 12 exhibited a reversible and thermosensitive phase transition in aqueous medium, from soluble to insoluble states. PMID:20938539

Uslu, Aylin; Güvenalt?n, Sener



Striatal cholinergic interneurons Drive GABA release from dopamine terminals.  


Striatal cholinergic interneurons are implicated in motor control, associative plasticity, and reward-dependent learning. Synchronous activation of cholinergic interneurons triggers large inhibitory synaptic currents in dorsal striatal projection neurons, providing one potential substrate for control of striatal output, but the mechanism for these GABAergic currents is not fully understood. Using optogenetics and whole-cell recordings in brain slices, we find that a large component of these inhibitory responses derive from action-potential-independent disynaptic neurotransmission mediated by nicotinic receptors. Cholinergically driven IPSCs were not affected by ablation of striatal fast-spiking interneurons but were greatly reduced after acute treatment with vesicular monoamine transport inhibitors or selective destruction of dopamine terminals with 6-hydroxydopamine, indicating that GABA release originated from dopamine terminals. These results delineate a mechanism in which striatal cholinergic interneurons can co-opt dopamine terminals to drive GABA release and rapidly inhibit striatal output neurons. PMID:24613418

Nelson, Alexandra B; Hammack, Nora; Yang, Cindy F; Shah, Nirao M; Seal, Rebecca P; Kreitzer, Anatol C



Implications of paraquat and hydrogen peroxide-induced oxidative stress treatments on the GABA shunt pathway in Arabidopsis thaliana calmodulin mutants  

Microsoft Academic Search

Arabidopsis mutants with T-DNA insertion in seven calmodulin genes (CAM) were used to determine the specific role of CAM in the tolerance of plants to oxidative stress induced by paraquat and hydrogen\\u000a peroxide (H2O2) treatments. Arabidopsis calmodulin mutants (cam) were screened for seedling growth, seed germination, induced oxidative damage, and levels of ?-aminobutyric acid (GABA)\\u000a shunt metabolites. Only the cam5-4

Nisreen A. AL-QuraanRobert; Robert D. Locy; Narendra K. Singh



Symbiosis between in vivo and in vitro NMR spectroscopy: The creatine, N-acetylaspartate, glutamate, and GABA content of the epileptic human brain  

Microsoft Academic Search

High resolution 1H NMR spectroscopy was used to analyze temporal lobe biopsies obtained from patients with epilepsy. Heat-stabilized cerebrum, dialyzed cytosolic macromolecules, and perchloric acid extracts were studied using one- and two dimensional spectroscopy. Anterior temporal lobe neocortex was enriched in GABA, glutamate, alanine, N-acetylaspartate, and creatine. Subjacent white matter was enriched in aspartate, glutamine, and inositol. The N-acetylaspartate\\/creatine mole

Ognen A. C. Petroff; Lisa A. Pleban; Dennis D. Spencer



GABA Not Only a Neurotransmitter: Osmotic Regulation by GABAAR Signaling  

PubMed Central

Mature macroglia and almost all neural progenitor types express ?-aminobutyric (GABA) A receptors (GABAARs), whose activation by ambient or synaptic GABA, leads to influx or efflux of chloride (Cl?) depending on its electro-chemical gradient (ECl). Since the flux of Cl? is indissolubly associated to that of osmotically obliged water, GABAARs regulate water movements by modulating ion gradients. In addition, since water movements also occur through specialized water channels and transporters, GABAAR signaling could affect the movement of water by regulating the function of the channels and transporters involved, thereby affecting not only the direction of the water fluxes but also their dynamics. We will here review recent observations indicating that in neural cells GABAAR-mediated osmotic regulation affects the cellular volume thereby activating multiple intracellular signaling mechanisms important for cell proliferation, maturation, and survival. In addition, we will discuss evidence that the osmotic regulation exerted by GABA may contribute to brain water homeostasis in physiological and in pathological conditions causing brain edema, in which the GABAergic transmission is often altered. PMID:22319472

Cesetti, Tiziana; Ciccolini, Francesca; Li, Yuting



A metabonomic study of inhibition of GABA uptake in the cerebral cortex  

Microsoft Academic Search

GABAergic activity is regulated by rapid, high affinity uptake of GABA from the synapse. Perturbation of GABA reuptake has\\u000a been implicated in neurological disease and inhibitors of GABA transporters (GAT) have been used therapeutically but little\\u000a detail is known about the ramifications of GAT inhibition on brain neurochemistry. Here, we incubated Guinea pig cortical\\u000a tissue slices with [3-13C]pyruvate and major,

Fatima A. Nasrallah; Vladimir J. Balcar; Caroline Rae



Nitric oxide stimulates gamma-aminobutyric acid release and inhibits glycine release in retina.  


Nitric oxide (NO) modulates the uptake and/or release of neurotransmitters through a variety of cellular mechanisms. However, the pharmacological and biochemical processes underlying these neurochemical effects of NO often remain unclear. In our study, we used immunocytochemical methods to study the effects of NO, cyclic guanosine monophosphate (cGMP), and peroxynitrite on the uptake and release of gamma-aminobutyric acid (GABA) and glycine in the turtle retina. In addition, we examined the involvement of glutamate receptors, calcium, and the GABA transporter in this GABA uptake and release. We also tested for interactions between the GABAergic and glycinergic systems. In general, we show that NO stimulated GABA release and inhibited glycine release. The NO-stimulated GABA release involved calcium-dependent or calcium-independent synaptic release or reversal of the GABA transporter. Some effects of NO on GABA release involved glutamate, cGMP, or peroxynitrite. NO promoted glycine uptake and inhibited its release, and this inhibition of glycine release was influenced by GABAergic modulation. These findings indicate that NO modulates the levels of the inhibitory transmitters GABA and glycine through several specific biochemical mechanisms in different retinal cell types and layers. Thus it appears that some of the previously described reciprocal interactions between GABA and glycine in the retina function through specific NO signaling pathways. PMID:15682393

Yu, Dou; Eldred, William D



Nitric Oxide Stimulates ?-Aminobutyric Acid Release and Inhibits Glycine Release in Retina  

PubMed Central

Nitric oxide (NO) modulates the uptake and/or release of neurotransmitters through a variety of cellular mechanisms. However, the pharmacological and biochemical processes underlying these neurochemical effects of NO often remain unclear. In our study, we used immunocytochemical methods to study the effects of NO, cyclic guanosine monophosphate (cGMP), and peroxynitrite on the uptake and release of ?-aminobutyric acid (GABA) and glycine in the turtle retina. In addition, we examined the involvement of glutamate receptors, calcium, and the GABA transporter in this GABA uptake and release. We also tested for interactions between the GABAergic and glycinergic systems. In general, we show that NO stimulated GABA release and inhibited glycine release. The NO-stimulated GABA release involved calcium-dependent or calcium-independent synaptic release or reversal of the GABA transporter. Some effects of NO on GABA release involved glutamate, cGMP, or peroxynitrite. NO promoted glycine uptake and inhibited its release, and this inhibition of glycine release was influenced by GABAergic modulation. These findings indicate that NO modulates the levels of the inhibitory transmitters GABA and glycine through several specific biochemical mechanisms in different retinal cell types and layers. Thus it appears that some of the previously described reciprocal interactions between GABA and glycine in the retina function through specific NO signaling pathways. PMID:15682393




MS transport assays for ?-aminobutyric acid transporters--an efficient alternative for radiometric assays.  


Transport assays for neurotransmitters based on radiolabeled substrates are widely spread and often indispensable in basic research and the drug development process, although the use of radioisotopes is inherently coupled to issues concerning radioactive waste and safety precautions. To overcome these disadvantages, we developed mass spectrometry (MS)-based transport assays for ?-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system (CNS). These "MS Transport Assays" provide all capabilities of [(3)H]GABA transport assays and therefore represent the first substitute for the latter. The performance of our approach is demonstrated for GAT1, the most important GABA transporter (GAT) subtype. As GABA is endogenously present in COS-7 cells employed as hGAT1 expression system, ((2)H6)GABA was used as a substrate to differentiate transported from endogenous GABA. To record transported ((2)H6)GABA, a highly sensitive, short, robust, and reliable HILIC-ESI-MS/MS quantification method using ((2)H2)GABA as an internal standard was developed and validated according to the Center for Drug Evaluation and Research (CDER) guidelines. Based on this LC-MS quantification, a setup to characterize hGAT1 mediated ((2)H6)GABA transport in a 96-well format was established, that enables automated processing and avoids any sample preparation. The K(m) value for ((2)H6)GABA determined for hGAT1 is in excellent agreement with results obtained from [(3)H]GABA uptake assays. In addition, the established assay format enables efficient determination of the inhibitory potency of GAT1 inhibitors, is capable of identifying those inhibitors transported as substrates, and furthermore allows characterization of efflux. The approach described here combines the strengths of LC-MS/MS with the high efficiency of transport assays based on radiolabeled substrates and is applicable to all GABA transporter subtypes. PMID:25007119

Schmitt, Sebastian; Höfner, Georg; Wanner, Klaus T



Effect of ligustrazine on levels of amino acid neurotransmitters in rat striatum after cerebral ischemia-reperfusion injury.  


This study aimed to evaluate the effect of ligustrazine on levels of amino acid transmitters in the extracellular fluid of striatum following cerebral ischemia/reperfusion (I/R) in male Sprague-Dawley rats. A microdialysis cannula guide was implanted into the right striatum. After recovery, animals underwent a sham operation or middle cerebral artery occlusion (MCAO). Those that developed cerebral ischemia after MCAO were randomized to receive propylene glycol salt water and ligustrazine respectively. Striatal fluid samples were collected from all animals at 15-min intervals after treatment and were subjected to HPLC analysis of aspartic acid, glutamic acid, taurine, and ?-amino butyric acid. Upon the last sample collection, animals were sacrificed and brain tissue specimens were collected for triphenyltetrazolium chloride staining and NeuN staining. Compared with the sham operation, MCAO induced significant neurological deficits and increased striatal concentrations of the four neurotransmitters assessed in a time-dependent manner (P < 0.01). Ligustrazine effectively attenuated the detrimental effects of MCAO on the brain. These observations suggest that ligustrazine as a novel cerebral infarction-protective agent may have potential clinical implications for I/R-related brain damage. PMID:25159498

Han, Jin; Wan, Hai-Tong; Yang, Jie-Hong; Zhang, Yu-Yan; Ge, Li-Jun; Bie, Xiao-Dong



Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics  

PubMed Central

The central amygdala (CeA) has a role for mediating fear and anxiety responses. It is also involved in emotional imbalance caused by alcohol abuse and dependence and in regulating relapse to alcohol abuse. Growing evidences suggest that excitatory glutamatergic and inhibitory ?-aminobutyric acid-ergic (GABAergic) transmissions in the CeA are affected by chronic alcohol exposure. Human post-mortem CeA samples from male alcoholics (n = 9) and matched controls (n = 9) were assayed for the expression level of ionotropic glutamate and GABA-A receptors subunit mRNAs using quantitative real-time reverse transcription-PCR (RT-qPCR). Our data revealed that out of the 16 ionotropic glutamate receptor subunits, mRNAs encoding two AMPA [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid] receptor subunits GluA1 and GluA4; one kainate receptor subunit GluK2; one NMDA (N-methyl-D-aspartate) receptor subunit GluN2D and one delta receptor subunit GluD2 were significantly decreased in the CeA of alcoholics. In contrast, of the 19 GABA-A receptor subunits, only the mRNA encoding the ?2 subunit was significantly down-regulated in the CeA of the alcoholics as compared with control subjects. Our findings imply that the down-regulation of specific ionotropic glutamate and GABA-A receptor subunits in the CeA of alcoholics may represent one of the molecular substrates underlying the new balance between excitatory and inhibitory neurotransmission in alcohol dependence.

Jin, Zhe; Bhandage, Amol K.; Bazov, Igor; Kononenko, Olga; Bakalkin, Georgy; Korpi, Esa R.; Birnir, Bryndis



Allosteric modulators induce distinct movements at the GABA-binding site interface of the GABA-A receptor.  


Benzodiazepines (BZDs) and barbiturates exert their CNS actions by binding to GABA-A receptors (GABARs). The structural mechanisms by which these drugs allosterically modulate GABAR function, to either enhance or inhibit GABA-gated current, are poorly understood. Here, we used the substituted cysteine accessibility method to examine and compare structural movements in the GABA-binding site interface triggered by a BZD positive (flurazepam), zero (flumazenil) and negative (3-carbomethoxy-4-ethyl-6,7-dimethoxy-?-carboline, DMCM) modulator as well as the barbiturate pentobarbital. Ten residues located throughout the GABA-binding site interface were individually mutated to cysteine. Wild-type and mutant ?(1)?(2)?(2) GABARs were expressed in Xenopus laevis oocytes and functionally characterized using two-electrode voltage clamp. We measured and compared the rates of modification of the introduced cysteines by sulfhydryl-reactive methanethiosulfonate (MTS) reagents in the absence and presence of BZD-site ligands and pentobarbital. Flurazepam and DMCM each accelerated the rate of reaction at ?(1)R131C and slowed the rate of reaction at ?(1)E122C, whereas flumazenil had no effect indicating that simple occupation of the BZD binding site is not sufficient to cause movements near these positions. Therefore, BZD-induced movements at these residues are likely associated with the ability of the BZD to modulate GABAR function (BZD efficacy). Low, modulating concentrations of pentobarbital accelerated the rate of reaction at ?(1)S68C and ?(2)P206C, slowed the rate of reaction at ?(1)E122C and had no effect at ?(1)R131C. These findings indicate that pentobarbital and BZDs induce different movements in the receptor, providing evidence that the structural mechanisms underlying their allosteric modulation of GABAR function are distinct. PMID:21093460

Sancar, Feyza; Czajkowski, Cynthia



Status epilepticus enhances tonic GABA currents and depolarizes GABA reversal potential in dentate fast-spiking basket cells  

PubMed Central

Temporal lobe epilepsy is associated with loss of interneurons and inhibitory dysfunction in the dentate gyrus. While status epilepticus (SE) leads to changes in granule cell inhibition, whether dentate basket cells critical for regulating granule cell feedforward and feedback inhibition express tonic GABA currents (IGABA) and undergo changes in inhibition after SE is not known. We find that interneurons immunoreactive for parvalbumin in the hilar-subgranular region express GABAA receptor (GABAAR) ?-subunits, which are known to underlie tonic IGABA. Dentate fast-spiking basket cells (FS-BCs) demonstrate baseline tonic IGABA blocked by GABAAR antagonists. In morphologically and physiologically identified FS-BCs, tonic IGABA is enhanced 1 wk after pilocarpine-induced SE, despite simultaneous reduction in spontaneous inhibitory postsynaptic current (sIPSC) frequency. Amplitude of tonic IGABA in control and post-SE FS-BCs is enhanced by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), demonstrating the contribution of GABAAR ?-subunits. Whereas FS-BC resting membrane potential is unchanged after SE, perforated-patch recordings from FS-BCs show that the reversal potential for GABA currents (EGABA) is depolarized after SE. In model FS-BCs, increasing tonic GABA conductance decreased excitability when EGABA was shunting and increased excitability when EGABA was depolarizing. Although simulated focal afferent activation evoked seizurelike activity in model dentate networks with FS-BC tonic GABA conductance and shunting EGABA, excitability of identical networks with depolarizing FS-BC EGABA showed lower activity levels. Thus, together, post-SE changes in tonic IGABA and EGABA maintain homeostasis of FS-BC activity and limit increases in dentate excitability. These findings have implications for normal FS-BC function and can inform studies examining comorbidities and therapeutics following SE. PMID:23324316

Yu, Jiandong; Proddutur, Archana; Elgammal, Fatima S.; Ito, Takahiro



Combined therapy with GABA and proinsulin/alum acts synergistically to restore long-term normoglycemia by modulating T-cell autoimmunity and promoting ?-cell replication in newly diabetic NOD mice.  


Antigen-based therapies (ABTs) fail to restore normoglycemia in newly diabetic NOD mice, perhaps because too few ?-cells remain by the time that ABT-induced regulatory responses arise and spread. We hypothesized that combining a fast-acting anti-inflammatory agent with an ABT could limit pathogenic responses while ABT-induced regulatory responses arose and spread. ?-Aminobutyric acid (GABA) administration can inhibit inflammation, enhance regulatory T-cell (Treg) responses, and promote ?-cell replication in mice. We examined the effect of combining a prototypic ABT, proinsulin/alum, with GABA treatment in newly diabetic NOD mice. Proinsulin/alum monotherapy failed to correct hyperglycemia, while GABA monotherapy restored normoglycemia for a short period. Combined treatment restored normoglycemia in the long term with apparent permanent remission in some mice. Proinsulin/alum monotherapy induced interleukin (IL)-4- and IL-10-secreting T-cell responses that spread to other ?-cell autoantigens. GABA monotherapy induced moderate IL-10 (but not IL-4) responses to ?-cell autoantigens. Combined treatment synergistically reduced spontaneous type 1 T-helper cell responses to autoantigens, ABT-induced IL-4 and humoral responses, and insulitis, but enhanced IL-10 and Treg responses and promoted ?-cell replication in the islets. Thus, combining ABT with GABA can inhibit pathogenic T-cell responses, induce Treg responses, promote ?-cell replication, and effectively restore normoglycemia in newly diabetic NOD mice. Since these treatments appear safe for humans, they hold promise for type 1 diabetes intervention. PMID:25146474

Tian, Jide; Dang, Hoa; Nguyen, An Viet; Chen, Zheying; Kaufman, Daniel L



[The characteristics of the retinal absorption of labelled preparations of pikamilon and GABA].  


The velocity of absorption of GABA and its derivative picamilon carbon-labelled by isolated bovine retina has been studied. It is shown that maximal velocity of GABA and picamilon absorption falls at the second incubation minute, then it decreases. In all the cases the picamilon absorption velocity is higher than the GABA absorption velocity. With an increase of concentration in the incubation medium of the labeled preparation under study the absorption velocity of GABA remains practically unchanged, while that of picamilon slightly increases. PMID:2055321

Loga?, I M; Leus, N F; Rozanova, Z A



GABA Signaling Promotes Synapse Elimination and Axon Pruning in Developing Cortical Inhibitory Interneurons  

PubMed Central

Accumulating evidence indicates that GABA acts beyond inhibitory synaptic transmission and regulates the development of inhibitory synapses in the vertebrate brain, but the underlying cellular mechanism is not well understood. We have combined live imaging of cortical GABAergic axons across time scales from minutes to days with single-cell genetic manipulation of GABA release to examine its role in distinct steps of inhibitory synapse formation in the mouse neocortex. We have shown previously, by genetic knockdown of GABA synthesis in developing interneurons, that GABA signaling promotes the maturation of inhibitory synapses and axons. Here we found that a complete blockade of GABA release in basket interneurons resulted in an opposite effect, a cell-autonomous increase in axon and bouton density with apparently normal synapse structures. These results not only demonstrate that GABA is unnecessary for synapse formation per se but also uncover a novel facet of GABA in regulating synapse elimination and axon pruning. Live imaging revealed that developing GABAergic axons form a large number of transient boutons, but only a subset was stabilized. Release blockade led to significantly increased bouton stability and filopodia density, increased axon branch extension, and decreased branch retraction. Our results suggest that a major component of GABA function in synapse development is transmission-mediated elimination of subsets of nascent contacts. Therefore, GABA may regulate activity-dependent inhibitory synapse formation by coordinately eliminating certain nascent contacts while promoting the maturation of other nascent synapses. PMID:22219294

Wu, Xiaoyun; Fu, Yu; Knott, Graham; Lu, Jiangteng; Di Cristo, Graziella



GABA transporter function, oligomerization state, and anchoring: correlates with subcellularly resolved FRET  

PubMed Central

The mouse ?-aminobutyric acid (GABA) transporter mGAT1 was expressed in neuroblastoma 2a cells. 19 mGAT1 designs incorporating fluorescent proteins were functionally characterized by [3H]GABA uptake in assays that responded to several experimental variables, including the mutations and pharmacological manipulation of the cytoskeleton. Oligomerization and subsequent trafficking of mGAT1 were studied in several subcellular regions of live cells using localized fluorescence, acceptor photobleach Förster resonance energy transfer (FRET), and pixel-by-pixel analysis of normalized FRET (NFRET) images. Nine constructs were functionally indistinguishable from wild-type mGAT1 and provided information about normal mGAT1 assembly and trafficking. The remainder had compromised [3H]GABA uptake due to observable oligomerization and/or trafficking deficits; the data help to determine regions of mGAT1 sequence involved in these processes. Acceptor photobleach FRET detected mGAT1 oligomerization, but richer information was obtained from analyzing the distribution of all-pixel NFRET amplitudes. We also analyzed such distributions restricted to cellular subregions. Distributions were fit to either two or three Gaussian components. Two of the components, present for all mGAT1 constructs that oligomerized, may represent dimers and high-order oligomers (probably tetramers), respectively. Only wild-type functioning constructs displayed three components; the additional component apparently had the highest mean NFRET amplitude. Near the cell periphery, wild-type functioning constructs displayed the highest NFRET. In this subregion, the highest NFRET component represented ?30% of all pixels, similar to the percentage of mGAT1 from the acutely recycling pool resident in the plasma membrane in the basal state. Blocking the mGAT1 C terminus postsynaptic density 95/discs large/zona occludens 1 (PDZ)-interacting domain abolished the highest amplitude component from the NFRET distributions. Disrupting the actin cytoskeleton in cells expressing wild-type functioning transporters moved the highest amplitude component from the cell periphery to perinuclear regions. Thus, pixel-by-pixel NFRET analysis resolved three distinct forms of GAT1: dimers, high-order oligomers, and transporters associated via PDZ-mediated interactions with the actin cytoskeleton and/or with the exocyst. PMID:19948998

Moss, Fraser J.; Imoukhuede, P.I.; Scott, Kimberly; Hu, Jia; Jankowsky, Joanna L.; Quick, Michael W.



GABAA receptors in VTA mediate the morphine-induced release of ascorbic acid in rat nucleus accumbens.  


Local perfusion of morphine produces increased levels of extracellular ascorbic acid (AA) in the nucleus accumbens (NAc) of freely moving rats. However, the pathways that regulate morphine-induced AA release in the NAc are unclear. In the present study, we used high performance liquid chromatography with electrochemical detection (HPLC-ECD) to examine the effects of intra-ventral tegmental area (VTA) administration of a GABA(A) agonist and antagonist on morphine-induced increases in AA of the NAc. Also, using high performance liquid chromatography with fluorescent detection (HPLC-FD) and HPLC-ECD, the releases of ?-aminobutyric acid (GABA) and dopamine (DA) in the NAc induced by intra-VTA administration of a GABA(A) agonist and antagonist were also investigated. The results obtained showed that morphine (1 mM), locally perfused into the NAc, significantly increased AA release in the NAc and also GABA release. Intra-VTA infusion of bicuculline (150 ng/rat), a GABA receptor antagonist, not only abolished the enhanced extracellular AA and GABA levels produced by local perfusion of morphine but also decreased the basal release of extracellular GABA and increased the basal release of extracellular DA in the NAc. Muscimol (100 ng/rat), a GABA receptor agonist, affected the basal release of GABA and DA, but not the basal AA levels, or the morphine-induced changes in AA and GABA levels. These findings suggest that the GABA(A) receptors in the VTA play an important role in the modulation of morphine-induced AA release in the NAc, and the effect of morphine on AA release in the NAc is partially regulated by the GABA(A) receptor-mediated action of DA afferents from the VTA. PMID:20965157

Sun, Ji-Ye; Yang, Jing-Yu; Wang, Fang; Hou, Yue; Dong, Ying-Xu; Wu, Chun-Fu



Synaptic inhibition and ?-aminobutyric acid in the mammalian central nervous system  

PubMed Central

Signal transmission through synapses connecting two neurons is mediated by release of neurotransmitter from the presynaptic axon terminals and activation of its receptor at the postsynaptic neurons. ?-Aminobutyric acid (GABA), non-protein amino acid formed by decarboxylation of glutamic acid, is a principal neurotransmitter at inhibitory synapses of vertebrate and invertebrate nervous system. On one hand glutamic acid serves as a principal excitatory neurotransmitter. This article reviews GABA researches on; (1) synaptic inhibition by membrane hyperpolarization, (2) exclusive localization in inhibitory neurons, (3) release from inhibitory neurons, (4) excitatory action at developmental stage, (5) phenotype of GABA-deficient mouse produced by gene-targeting, (6) developmental adjustment of neural network and (7) neurological/psychiatric disorder. In the end, GABA functions in simple nervous system and plants, and non-amino acid neurotransmitters were supplemented. PMID:23574805

OBATA, Kunihiko



The ontogeny of GABA and glutamate-like immunoreactivity in the embryonic Australian freshwater crayfish, Cherax destructor  

Microsoft Academic Search

The distribution and ontogeny of GABA- and glutamate-like immunoreactivity in embryos of the Australian freshwater crayfish Cherax destructor were investigated over the period from 30% development until hatching. GABA-like immunoreactive cells and fibres appeared first in the brain at 40–45% development. By 70% development, GABA-like immunoreactive cells were present in almost all ganglia, and GABA-like immunoreactive fibres were distributed extensively

Lisa C Foa; Ian R. C Cooke



Functioning of the dimeric GABA(B) receptor extracellular domain revealed by glycan wedge scanning  

E-print Network

34094 MONTPELLIER CEDEX 5,FR Sino-France Laboratory for Drug Screening2 Huazhong University of Science for trafficking GABA to the cell surface, increasing agonist affinity to GABA , andB1 B2 B1 B1 activating, and then showed that introducing an N-glycan at this interface prevents the association of the two subunits

Paris-Sud XI, Université de


GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes.  


Type 1 diabetes (T1D) is an autoimmune disease characterized by insulitis and islet ?-cell loss. Thus, an effective therapy may require ?-cell restoration and immune suppression. Currently, there is no treatment that can achieve both goals efficiently. We report here that GABA exerts antidiabetic effects by acting on both the islet ?-cells and immune system. Unlike in adult brain or islet ?-cells in which GABA exerts hyperpolarizing effects, in islet ?-cells, GABA produces membrane depolarization and Ca(2+) influx, leading to the activation of PI3-K/Akt-dependent growth and survival pathways. This provides a potential mechanism underlying our in vivo findings that GABA therapy preserves ?-cell mass and prevents the development of T1D. Remarkably, in severely diabetic mice, GABA restores ?-cell mass and reverses the disease. Furthermore, GABA suppresses insulitis and systemic inflammatory cytokine production. The ?-cell regenerative and immunoinhibitory effects of GABA provide insights into the role of GABA in regulating islet cell function and glucose homeostasis, which may find clinical application. PMID:21709230

Soltani, Nepton; Qiu, Hongmin; Aleksic, Mila; Glinka, Yelena; Zhao, Fang; Liu, Rui; Li, Yiming; Zhang, Nina; Chakrabarti, Rabindranath; Ng, Tiffany; Jin, Tianru; Zhang, Haibo; Lu, Wei-Yang; Feng, Zhong-Ping; Prud'homme, Gerald J; Wang, Qinghua



GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes  

PubMed Central

Type 1 diabetes (T1D) is an autoimmune disease characterized by insulitis and islet ?-cell loss. Thus, an effective therapy may require ?-cell restoration and immune suppression. Currently, there is no treatment that can achieve both goals efficiently. We report here that GABA exerts antidiabetic effects by acting on both the islet ?-cells and immune system. Unlike in adult brain or islet ?-cells in which GABA exerts hyperpolarizing effects, in islet ?-cells, GABA produces membrane depolarization and Ca2+ influx, leading to the activation of PI3-K/Akt–dependent growth and survival pathways. This provides a potential mechanism underlying our in vivo findings that GABA therapy preserves ?-cell mass and prevents the development of T1D. Remarkably, in severely diabetic mice, GABA restores ?-cell mass and reverses the disease. Furthermore, GABA suppresses insulitis and systemic inflammatory cytokine production. The ?-cell regenerative and immunoinhibitory effects of GABA provide insights into the role of GABA in regulating islet cell function and glucose homeostasis, which may find clinical application. PMID:21709230

Soltani, Nepton; Qiu, Hongmin; Aleksic, Mila; Glinka, Yelena; Zhao, Fang; Liu, Rui; Zhang, Nina; Chakrabarti, Rabindranath; Jin, Tianru; Zhang, Haibo; Lu, Wei-Yang; Feng, Zhong-Ping; Prud'homme, Gerald J.; Wang, Qinghua



GABA synapses mediate neuroprotection after ischemic and ?PKC preconditioning in rat hippocampal slice cultures  

Microsoft Academic Search

Delayed neuroprotection against ischemic challenges is conferred by both ischemic preconditioning (IPC) and preconditioning by activation of the ?-isoform of protein kinase C (?PKC-PC). In vivo, ischemic preconditioning enhances GABA release and ameliorates glutamate release during lethal cerebral ischemia. We tested the hypothesis that IPC and ?PKC-PC confer neuroprotection by GABA synapses in rat organotypic hippocampal slices. Ischemic preconditioning or

R Anthony DeFazio; Ami P Raval; Hung W Lin; Kunjan R Dave; David Della-Morte; Miguel A Perez-Pinzon



Elevated Endogenous GABA Concentration Attenuates Glutamate-Glutamine Cycling between Neurons and Astroglia  

PubMed Central

In this study, the relationship between endogenous brain GABA concentration and glutamate-glutamine cycling flux (Vcyc) was investigated using in vivo 1H and 1H{13C} magnetic resonance spectroscopy techniques. Graded elevations of brain GABA levels were induced in rat brain after administration of the highly specific GABA-transaminase inhibitor vigabatrin (?-vinyl-GABA). The glial-specific substrate [2-13C]acetate and 1H{13C} magnetic resonance spectroscopy were used to measure Vcyc at different GABA levels. Significantly reduced Vcyc was found in rats pretreated with vigabatrin. The reduction in group mean Vcyc over the range of GABA concentrations investigated in this study (1.0 ± 0.3 ~ 5.1 ± 0.5 ?mol/g) was found to be nonlinear: ?Vcyc/Vcyc = [GABA (?mol/g)]?0.35 ? 1.0 (r2 = 0.98). The results demonstrate that Vcyc is modulated by endogenous GABA levels, and that glutamatergic and GABAergic interactions can be studied in vivo using noninvasive magnetic resonance spectroscopy techniques. PMID:19184333

Yang, Jehoon; Shen, Jun



Combining Membrane Potential Imaging with L-Glutamate or GABA Photorelease  

E-print Network

Combining Membrane Potential Imaging with L-Glutamate or GABA Photorelease Kaspar E. Vogt1 with photolysis of L-glutamate or GABA allows the monitoring of electrical activity elicited potential changes by depolarising the dendrites of cerebellar Purkinje neurons with L-glutamate photorelease

Boyer, Edmond


Cell type specificity of GABA(A) receptor mediated signaling in the hippocampus.  


Inhibitory signaling mediated by ionotropic GABA(1) receptors generally acts as a major brake against excessive excitability in the brain. This is especially relevant in epilepsy-prone structures such as the hippocampus, in which GABA(A) receptor mediated inhibition is critical in suppressing epileptiform activity. Indeed, potentiating GABA(A) receptor mediated signaling is an important target for antiepileptic drug therapy. GABA(A) receptor mediated inhibition has different roles in the network dependent on the target neuron. Inhibiting principal cells will thus reduce network excitability, whilst inhibiting interneurons will increase network excitability; GABAergic therapeutic agents do not distinguish between these two alternatives, which may explain why, on occasion, GABAergic antiepileptic drugs can be proconvulsant. The importance of the target-cell for the effect of neuroactive drugs has emerged from a number of recent studies. Immunocytochemical data have suggested non-uniform distribution of GABA(A) receptor subunits among hippocampal interneurons and pyramidal cells. This has been confirmed by subsequent electropharmacological data. These have demonstrated that compounds which act on GABA(A) receptors or the extracellular GABA concentration can have distinct effects in different neuronal populations. Recently, it has also been discovered that presynaptic glutamate heteroreceptors can modulate GABA release in the hippocampus in a postsynaptic cell-specific manner. Since systemically administrated drugs may act on different neuronal subtypes, they can exhibit paradoxical effects. Distinguishing compounds that have target specific effects on GABAergic signaling may lead to novel and more effective treatments against epilepsy. PMID:12871034

Semyanov, A



Coexistence of Excitatory and Inhibitory GABA Synapses in the Cerebellar Interneuron Network  

Microsoft Academic Search

Functional GABA synapses are usually assumed to be inhibitory. However, we show here that inhibitory and excitatory GABA connec- tions coexist in the cerebellar interneuron network. The reversal potential of GABAergic currents (EGABA ) measured in interneurons is relatively depolarized and contrasts with the hyperpolarized value found in Purkinje cells (58 and85 mV respectively). This finding is not correlated to

Joël Chavas; Alain Marty



GABA uptake regulates cortical excitability via cell type–specific tonic inhibition  

Microsoft Academic Search

GABAA receptors can mediate both 'phasic' synaptic inhibition and a persistent 'tonic' form of signaling. We show that, in the presence of intact GABA uptake, guinea pig hippocampal interneurons, but not pyramidal cells, express a tonic GABAA receptor–mediated conductance. This conductance was pharmacologically distinct from spontaneous inhibitory postsynaptic currents (IPSCs). Inhibiting GABA uptake resulted in the expression of a comparable

Alexey Semyanov; Matthew C. Walker; Dimitri M. Kullmann



Metabolism of hibernating reptiles. Changes of free amino acids in blood, liver and brain.  


1. Glutamic acid showed a significant decrease during hibernation in brain cortex. This is attributed to: (a) Transformation to glutamine to detoxicate ammonia. (b) The synthesis of GABA from glutamic acid. (c) It is suggested that the enzyme GAD is active during hibernation. 2. GABA showed a significant increase in liver and brain cortex. It was absent in the blood serum. (a) The present results show that non-neural tissues contain lower GABA than neural tissues. (b) GABA may be formed locally in tissues by decarboxylation of glutamate as well as from pathways connected with tricarboxylic acid cycle. 3. Aspartic acid showed increased levels in blood serum, liver and brain cortex, the greatest increase was observed in liver. 4. A significant increase was recorded in the level of arginine in brain cortex and liver, whilst a smaller percentage increase was recorded in ornithine level. It is assumed that transformation of arginine to ornithine was depressed during hibernation. PMID:318310

Raheem, K A; el Mosallamy, N



Genetic disorders of gamma-aminobutyric acid, glycine, and serine as causes of epilepsy.  


Genetic disorders of gamma-aminobutyric acid (GABA), glycine, and serine metabolism and of the GABA and glycine receptors are causes of epilepsy with variable responsiveness to treatment. Pyridoxine-dependent convulsions and the GABA(A) receptor defects are pure epileptic disorders that respond well to treatment. The convulsions associated with 3-phosphoglycerate dehydrogenase deficiency can be completely abolished with amino acid therapy. Epilepsy is a major symptom in succinic semialdehyde dehydrogenase deficiency. The convulsions in these disorders are not responsive or are only partially responsive to treatment. PMID:12597057

Jaeken, Jaak



Inhibitors of the ?-Aminobutyric Acid Transporter 1 (GAT1) Do Not Reveal a Channel Mode of Conduction  

PubMed Central

We expressed the ?-aminobutyric acid (GABA) transporter GAT1 (SLC6A1) in Xenopus laevis oocytes and performed GABA uptake experiments under voltage clamp at different membrane potentials as well as in the presence of the specific GAT1 inhibitors SKF-89976A and NO-711. In the absence of the inhibitors, GAT1 mediated the inward translocation of 2 net positive charges across the plasma membrane for every GABA molecule transported into the cell. This 2:1 charge flux / GABA flux ratio was the same over a wide range of membrane potentials from ?110 mV to +10 mV. Moreover, when GABA-evoked (500 ?M) currents were measured at ?50 and ?90 mV, neither SKF-89976A (5 and 25 ?M) nor NO-711 (2 ?M) altered the 2:1 charge flux / GABA flux ratio. The results are not consistent with previous hypotheses that (i) GABA evokes an uncoupled channel-mediated current in GAT1, and (ii) GAT1 inhibitors block the putative uncoupled current gated by GABA. Rather, the results suggest tight coupling of GAT1-mediated charge flux and GABA flux. PMID:19622377

Matthews, Edward; Rahnama-Vaghef, Ali; Eskandari, Sepehr



Valproate improves prepulse inhibition deficits induced by corticotropin-releasing factor independent of GABA(A) and GABA(B) receptor activation.  


Corticotropin-releasing factor (CRF) is implicated in the pathogenesis of bipolar disorder, an illness associated with deficits in prepulse inhibition (PPI) of the acoustic startle response. Valproate is used in the treatment of bipolar disorder and may alter CRF activity via a GABA(A)-ergic mechanism. This study determined the effect of valproate on CRF-disrupted PPI and examined the role of the hypothalamic-pituitary-adrenal axis and GABA-ergic signaling in the effect of valproate. Valproate (60-240 mg/kg) dose-dependently reversed PPI deficits displayed by transgenic mice overexpressing CRF (CRFtg), and normalized PPI deficits induced by CRF i.c.v. infusion in 129Sv mice. Valproate enhanced corticosterone secretion more effectively in CRFtg than in wild-type mice. The effect of valproate on PPI was not blocked by the GABA(A) receptor antagonist bicuculline, the GABA(B) receptor antagonists phaclofen and SCH 50911 or combined administration of a GABA(A) and GABA(B) receptor antagonist. The beneficial effect of valproate on PPI was not mimicked by the GABA(A) receptor agonist muscimol, the GABA transaminase inhibitor vigabatrin, the histone deacetylase (HDAC) inhibitor sodium butyrate or by the mood stabilizers lithium, carbamazepine, lamotrigine or topiramate. Thus, we showed that valproate improves CRF-induced PPI deficits, albeit via a so far unknown mechanism. These marked beneficial effects of valproate on CRF-induced sensorimotor gating deficits suggest that valproate may be of particular value in specific subgroups of bipolar patients that are characterized by alterations in the CRF system. PMID:24211652

T N, Douma; M J, Millan; P M, Verdouw; R S, Oosting; B, Olivier; L, Groenink



Endospore abundance and D:L-amino acid modeling of bacterial turnover in holocene marine sediment (Aarhus Bay)  

NASA Astrophysics Data System (ADS)

In order to study bacterial activity, and turnover times of bacterial necromass and biomass in marine sediment, two stations from the Aarhus Bay, Denmark were analyzed. Sediment cores were up to 11 m deep and covered a timescale from the present to ˜11,000 years ago. Sediment was analyzed for total hydrolysable amino acids (THAA), total hydrolysable amino sugars, the bacterial endospore marker dipicolinic acid (DPA), and amino acid enantiomers (L- and D-form) of aspartic acid. Turnover times of bacterial necromass and vegetative cells, as well as carbon oxidation rates were estimated by use of the D:L-amino acid racemization model. Diagenetic indicators were applied to evaluate the diagenetic state of the sedimentary organic matter. The contribution of amino acids to total organic carbon, and the ratio between the amino acids aspartic acid and glutamic acid, and their respective non protein degradation products, ?-alanine and ?-amino butyric acid, all indicated increasing degradation state of the organic matter with sediment depth and age. Quantification of DPA showed that endospores were abundant, and increased with depth relative to vegetative cells. Most of the amino acids (97%) could be ascribed to microbial necromass, i.e. the remains of dead bacterial cells. Model estimates showed that the turnover times of microbial necromass were in the range of 0.5-1 × 105 years, while turnover times of vegetative cells were in the range of tens to hundreds of years. The turnover time of the TOC pool increased with depth in the sediment, indicating that the TOC pool became progressively more refractory and unavailable to microorganisms with depth and age of the organic matter.

Langerhuus, Alice T.; Røy, Hans; Lever, Mark A.; Morono, Yuki; Inagaki, Fumio; Jørgensen, Bo B.; Lomstein, Bente Aa.



Sorting of the Vesicular GABA Transporter to Functional Vesicle Pools by an Atypical Dileucine-like Motif  

PubMed Central

Increasing evidence indicates that individual synaptic vesicle proteins may use different signals, endocytic adaptors, and trafficking pathways for sorting to distinct pools of synaptic vesicles. Here, we report the identification of a unique amino acid motif in the vesicular GABA transporter (VGAT) that controls its synaptic localization and activity-dependent recycling. Mutational analysis of this atypical dileucine-like motif in rat VGAT indicates that the transporter recycles by interacting with the clathrin adaptor protein AP-2. However, mutation of a single acidic residue upstream of the dileucine-like motif leads to a shift to an AP-3-dependent trafficking pathway that preferentially targets the transporter to the readily releasable and recycling pool of vesicles. Real-time imaging with a VGAT-pHluorin fusion provides a useful approach to explore how unique sorting sequences target individual proteins to synaptic vesicles with distinct functional properties. PMID:23804087

Santos, Magda S.; Park, C. Kevin; Foss, Sarah M.; Li, Haiyan



?-Aminobutyric acid induces resistance against Penicillium expansum by priming of defence responses in pear fruit.  


The results from this study showed that treatment with ?-aminobutyric acid (GABA), at 100-1000 ?g/ml, induced strong resistance against blue mould rot caused by Penicillium expansum in pear fruit. Moreover, the activities of five defence-related enzymes (including chitinase, ?-1,3-glucanase, phenylalnine ammonialyase, peroxidase and polyphenol oxidase) and the expression of these corresponding genes were markedly and/or promptly enhanced in the treatment with GABA and inoculation with P. expansum compared with those that were treated with GABA or inoculated with pathogen alone. In addition, the treatment of pear with GABA had little adverse effect on the edible quality of the fruit. To the best of our knowledge, this is the first report that GABA can effectively reduce fungal disease of harvested fruit. Its mechanisms may be closely correlated with the induction of fruit resistance by priming activation and expression of defence-related enzymes and genes upon challenge with pathogen. PMID:24767023

Yu, Chen; Zeng, Lizhen; Sheng, Kuang; Chen, Fangxia; Zhou, Tao; Zheng, Xiaodong; Yu, Ting



Tonic control of kisspeptin release in prepubertal monkeys: implications to the mechanism of puberty onset.  


Previously we have shown that a reduction in ?-amino butyric acid (GABA) inhibition is critical for the mechanism initiating puberty onset because chronic infusion of the GABA(A) receptor antagonist, bicuculline, significantly increased GnRH release and accelerated the timing of menarche and first ovulation in female rhesus monkeys. Because previous studies in our laboratory indicate that in prepubertal female monkeys, kisspeptin release in the medial basal hypothalamus is low, whereas kisspeptin-10 can stimulate GnRH release, we hypothesized that a low level of kisspeptin release prior to puberty onset is due to tonic GABA inhibition. To test this hypothesis we examined the effects of bicuculline infusion on kisspeptin release using a microdialysis method. We found that bicuculline at 1 ?M dramatically stimulates kisspeptin release in the medial basal hypothalamus of prepubertal monkeys but had little effect on kisspeptin release in midpubertal monkeys. We further examined whether bicuculline-induced GnRH release is blocked by the presence of the kisspeptin antagonist, peptide 234. We found that inhibition of kisspeptin signaling blocked the bicuculline-induced stimulation of GnRH release, suggesting that kisspeptin neurons may relay inhibitory GABA signals to GnRH neurons. This implies that a reduction in tonic GABA inhibition of GnRH release is, at least in part, mediated through kisspeptin neurons. PMID:22585828

Kurian, Joseph R; Keen, Kim L; Guerriero, Kathryn A; Terasawa, Ei



Anxiolytic effect of Kami-Shoyo-San (TJ-24) in mice: possible mediation of neurosteroid synthesis.  


We assessed the anxiolytic effect of Kami-Shoyo-San (Jia-wei-xiao-yao-san; TJ-24), one of a traditional Chinese herbal medicine used for the treatment of menopausal anxiety, by the social interaction (SI) test in male mice. Acute administration of TJ-24 (25-100 mg/kg, p.o.), as well as the gamma-amino-butyric acidA/benzodiazepine (GABA(A)/BZP) receptor agonist diazepam (1-3 mg/kg, i.p.), dose dependently increased the SI time, respectively. The GABA(A) receptor antagonist picrotoxin blocked the effects of TJ-24 and diazepam. TJ-24-induced SI behavior was significantly blocked by the GABA(A)/BZP receptor inverse agonist Ro 15-4513 and the GABA(A)/BZP receptor antagonist flumazenil. In addition, 5alpha-reductase inhibitor finasteride potently blocked the effect of TJ-24 without attenuating the basal level by itself. These findings suggest that TJ-24 shows the anxiolytic effect through the neurosteroid synthesis followed by GABA(A)/BDZ receptor stimulations. PMID:11669460

Mizowaki, M; Toriizuka, K; Hanawa, T



Limitations of Current GABA Agonists in Neonatal Seizures: Toward GABA Modulation Via the Targeting of Neuronal Cl? Transport  

PubMed Central

Neonatal intensive care has advanced rapidly in the last 40?years, with dramatic decreases in mortality and morbidity; however, for neonatal seizures, neither therapies nor outcomes have changed significantly. Basic and clinical studies indicate that seizures in neonates have long-term neurodevelopmental and psychiatric consequences, highlighting the need for novel pharmacotherapeutics. First-line treatments targeting GABAA receptors, like barbiturates and benzodiazepines, are limited in their efficacy and carry significant risks to the developing brain. Here, we review the use of current GABA agonist therapies for neonatal seizures and suggest other treatment strategies given recent developments in the understanding of disease pathogenesis. One promising avenue is the indirect manipulation of the GABAergic system, via the modulation of neuronal Cl? gradients, by targeting the cation-Cl? cotransporters (NKCC1 and KCC2) or their regulatory signaling molecules. This strategy might yield a novel class of more efficacious anti-epileptics with fewer side effects by specifically addressing disease pathophysiology. Moreover, this strategy may have ramifications for other adult seizure syndromes in which GABA receptor-mediated depolarizations play a pathogenic role, such as temporal lobe epilepsy. PMID:23805124

Khanna, Arjun; Walcott, Brian Patrick; Kahle, Kristopher T.



Limitations of Current GABA Agonists in Neonatal Seizures: Toward GABA Modulation Via the Targeting of Neuronal Cl(-) Transport.  


Neonatal intensive care has advanced rapidly in the last 40?years, with dramatic decreases in mortality and morbidity; however, for neonatal seizures, neither therapies nor outcomes have changed significantly. Basic and clinical studies indicate that seizures in neonates have long-term neurodevelopmental and psychiatric consequences, highlighting the need for novel pharmacotherapeutics. First-line treatments targeting GABAA receptors, like barbiturates and benzodiazepines, are limited in their efficacy and carry significant risks to the developing brain. Here, we review the use of current GABA agonist therapies for neonatal seizures and suggest other treatment strategies given recent developments in the understanding of disease pathogenesis. One promising avenue is the indirect manipulation of the GABAergic system, via the modulation of neuronal Cl(-) gradients, by targeting the cation-Cl(-) cotransporters (NKCC1 and KCC2) or their regulatory signaling molecules. This strategy might yield a novel class of more efficacious anti-epileptics with fewer side effects by specifically addressing disease pathophysiology. Moreover, this strategy may have ramifications for other adult seizure syndromes in which GABA receptor-mediated depolarizations play a pathogenic role, such as temporal lobe epilepsy. PMID:23805124

Khanna, Arjun; Walcott, Brian Patrick; Kahle, Kristopher T



Identification and Characterization of ?-Aminobutyric Acid Uptake System GabPCg (NCgl0464) in Corynebacterium glutamicum  

PubMed Central

Corynebacterium glutamicum is widely used for industrial production of various amino acids and vitamins, and there is growing interest in engineering this bacterium for more commercial bioproducts such as ?-aminobutyric acid (GABA). In this study, a C. glutamicum GABA-specific transporter (GabPCg) encoded by ncgl0464 was identified and characterized. GabPCg plays a major role in GABA uptake and is essential to C. glutamicum growing on GABA. GABA uptake by GabPCg was weakly competed by l-Asn and l-Gln and stimulated by sodium ion (Na+). The Km and Vmax values were determined to be 41.1 ± 4.5 ?M and 36.8 ± 2.6 nmol min?1 (mg dry weight [DW])?1, respectively, at pH 6.5 and 34.2 ± 1.1 ?M and 67.3 ± 1.0 nmol min?1 (mg DW)?1, respectively, at pH 7.5. GabPCg has 29% amino acid sequence identity to a previously and functionally identified aromatic amino acid transporter (TyrP) of Escherichia coli but low identities to the currently known GABA transporters (17% and 15% to E. coli GabP and Bacillus subtilis GabP, respectively). The mutant RES167 ?ncgl0464/pGXKZ9 with the GabPCg deletion showed 12.5% higher productivity of GABA than RES167/pGXKZ9. It is concluded that GabPCg represents a new type of GABA transporter and is potentially important for engineering GABA-producing C. glutamicum strains. PMID:22307305

Zhao, Zhi; Ma, Wen-hua; Zhou, Ning-Yi



Quantitative changes of GABA-immunoreactive cells in the hindlimb representation of the rat somatosensory cortex after 14-day hindlimb unloading by tail suspension  

NASA Technical Reports Server (NTRS)

The present study was aimed at evaluating quantitatively gamma-aminobutyric acid (GABA) immunoreactivity in the hindlimb representation of the rat somatosensory cortex after 14 days of hindlimb unloading by tail suspension. A reduction in the number of GABA-immunoreactive cells with respect to the control animals was observed in layer Va and Vb. GABA-containing terminals were also reduced in the same layers, particularly those terminals surrounding the soma and apical dendrites of pyramidal cells in layer Vb. On the basis of previous morphological and behavioral studies of the neuromuscular system of hindlimb-suspended animals, it is suggested that the unloading due to hindlimb suspension alters afferent signaling and feedback information from intramuscular receptors to the cerebral cortex due to modifications in the reflex organization of hindlimb muscle groups. We propose that the reduction in immunoreactivity of local circuit GABAergic neurons and terminals is an expression of changes in their modulatory activity to compensate for the alterations in the afferent information.

D'Amelio, F.; Fox, R. A.; Wu, L. C.; Daunton, N. G.



Low expression of the ClC-2 chloride channel during postnatal development: a mechanism for the paradoxical depolarizing action of GABA and glycine in the hippocampus.  

PubMed Central

In early postnatal development, during the period of synapse formation, gamma-aminobutyric acid (GABA) and glycine, the main inhibitory transmitters in the adult brain, paradoxically excite and depolarize neuronal membranes by an outward flux of chloride. The mechanisms of chloride homeostasis are not fully understood. It is known that in adult neurons intracellular chloride accumulation is prevented by a particular type of chloride channel, the ClC-2. This channel strongly rectifies in the inward direction at potentials negative to ECl thus ensuring chloride efflux. We have tested the hypothesis that in the developing hippocampus, a differential expression or regulation of ClC-2 channels may contribute to the depolarizing action of GABA and glycine. We have cloned a truncated form of ClC-2 (ClC-2nh) from the neonatal hippocampus which lacks the 157 bp corresponding to exon 2. In situ hybridization experiments show that ClC-2nh is the predominant form of ClC-2 mRNA in the neonatal brain. ClC-2nh mRNA is unable to encode a full-length protein due to a frameshift, consequently it does not induce any currents upon injection into Xenopus oocytes. Low expression of the full-length ClC-2 channel, could alter chloride homeostasis, lead to accumulation of [Cl-]i and thereby contribute to the depolarizing action of GABA and glycine during early development. PMID:10418163

Mladinic, M; Becchetti, A; Didelon, F; Bradbury, A; Cherubini, E



GABA transient sets the susceptibility of mIPSCs to modulation by benzodiazepine receptor agonists in rat hippocampal neurons.  


Benzodiazepines (BDZs) are known to increase the amplitude and duration of IPSCs. Moreover, at low [GABA], BDZs strongly enhance GABAergic currents suggesting the up-regulation of agonist binding while their action on gating remains a matter of debate. In the present study we have examined the impact of flurazepam and zolpidem on mIPSCs by investigating their effects on GABA(A)R binding and gating and by considering dynamic conditions of synaptic receptor activation. Flurazepam and zolpidem enhanced the amplitude and prolonged decay of mIPSCs. Both compounds strongly enhanced responses to low [GABA] but, surprisingly, decreased the currents evoked by saturating or half-saturating [GABA]. Analysis of current responses to ultrafast GABA applications indicated that these compounds enhanced binding and desensitization of GABA(A) receptors. Flurazepam and zolpidem markedly prolonged deactivation of responses to low [GABA] but had almost no effect on deactivation at saturating or half-saturating [GABA]. Moreover, at low [GABA], flurazepam enhanced desensitization-deactivation coupling but zolpidem did not. Recordings of responses to half-saturating [GABA] applications revealed that appropriate timing of agonist exposure was sufficient to reproduce either a decrease or enhancement of currents by flurazepam or zolpidem. Recordings of currents mediated by recombinant ('synaptic') alpha1beta2gamma2 receptors reproduced all major findings observed for neuronal GABA(A)Rs. We conclude that an extremely brief agonist transient renders IPSCs particularly sensitive to the up-regulation of agonist binding by BDZs. PMID:17855751

Mozrzymas, Jerzy W; Wójtowicz, Tomasz; Piast, Michal; Lebida, Katarzyna; Wyrembek, Paulina; Mercik, Katarzyna



Regional GABA/benzodiazepine receptor/chloride channel coupling after acute and chronic benzodiazepine treatment.  


GABA/benzodiazepine coupling was evaluated in 8 regions of rat brain by the ability of GABA to stimulate 0.5 nM [3H]flunitrazepam binding. Rats were treated acutely with diazepam (p.o) or chronically with flurazepam, offered in the drinking water for 4 weeks, and compared to a pair-handled vehicle-treated control group. Regional variations in GABA/benzodiazepine coupling were found in control membranes. GABA increased benzodiazepine binding maximally (40%) in cerebellum and medulla, and least (25%) in olfactory bulb. A significant decrease in the effect of GABA was found in cortex of chronically treated rats immediately after, but not 2 days following treatment. The Emax for GABA stimulation of [3H]flunitrazepam binding was significantly increased in medulla after acute treatment but was not altered after acute or chronic treatment in other brain areas evaluated. Treatment had no effect on the ability of bicuculline to inhibit [3H]flunitrazepam binding in cortex. Benzodiazepine/Cl- coupling in cortex or hippocampus of acutely and chronically treated rats, evaluated by the ability of Cl- to stimulate specific [3H]flunitrazepam binding, was not changed. The results support the hypothesis that a functional uncoupling of the benzodiazepine recognition site from the GABA receptor in cortex, but not from the anion recognition site, may play a role in tolerance development. PMID:2476326

Tietz, E I; Chiu, T H; Rosenberg, H C



Regulation of GABA and benzodiazepine receptors following neurotoxin-induced striatal and medial forebrain bundle lesions  

SciTech Connect

GABA, a major inhibitory transmitter, is used by many projection neurons of the striatum. To investigate the role of GABA in striatal function, the GABA receptor complex was studied after lesions of the striatum or the nigrostriatal neurons. Quantitative receptor autoradiography using thaw-mounted tissue slices was developed for the study of GABA and benzodiazepine (BDZ) receptors. With the technique established, binding to GABA and BDZ receptors after unilateral striatal kainate lesions was examined. Subsequently, changes in GABA and BDZ receptors were studied following the destruction of dopaminergic nigrostriatal cells by unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. In summary, quantitative receptor autoradiography allowed the detection of GABA and BDZ receptor changes in multiple small areas in each lesioned brain. This technique made it feasible to carry out kinetic saturation, and competition studies using less than 1 mg of tissue. The data suggest that dopamine is functionally inhibitory on striatopallidal neurons but is functionally excitatory on striatoentopeduncular and striatonigral cells which in turn inhibit the thalamus. This quantitative autoradiographic technique can be generalized to study other transmitter receptors and can be combined with 2-deoxyglucose uptake studies.

Pan, H.S.I.



Identification and characterization of GABA(A) receptor autoantibodies in autoimmune encephalitis.  


Autoimmune forms of encephalitis have been associated with autoantibodies against synaptic cell surface antigens such as NMDA- and AMPA-type glutamate receptors, GABA(B) receptor, and LGI1. However, it remains unclear how many synaptic autoantigens are yet to be defined. Using immunoproteomics, we identified autoantibodies against the GABA(A) receptor in human sera from two patients diagnosed with encephalitis who presented with cognitive impairment and multifocal brain MRI abnormalities. Both patients had antibodies directed against the extracellular epitope of the ?3 subunit of the GABA(A) receptor. The ?3-subunit-containing GABA(A) receptor was a major target of the patients' serum antibodies in rat hippocampal neurons because the serum reactivity to the neuronal surface was greatly decreased by 80% when the ?3 subunit was knocked down. Our developed multiplex ELISA testing showed that both patients had similar levels of GABA(A) receptor antibodies, one patient also had a low level of LGI1 antibodies, and the other also had CASPR2 antibodies. Application of the patients' serum at the time of symptom presentation of encephalitis to rat hippocampal neuron cultures specifically decreased both synaptic and surface GABA(A) receptors. Furthermore, treatment of neurons with the patients' serum selectively reduced miniature IPSC amplitude and frequency without affecting miniature EPSCs. These results strongly suggest that the patients' GABA(A) receptor antibodies play a central role in the patients' symptoms. Therefore, this study establishes anti-GABA(A) receptor encephalitis and expands the pathogenic roles of GABA(A) receptor autoantibodies. PMID:24920620

Ohkawa, Toshika; Satake, Shin'Ichiro; Yokoi, Norihiko; Miyazaki, Yu; Ohshita, Tomohiko; Sobue, Gen; Takashima, Hiroshi; Watanabe, Osamu; Fukata, Yuko; Fukata, Masaki



Characteristic development of the GABA-removal system in the mouse spinal cord.  


GABA is a predominant inhibitory neurotransmitter in the CNS. Released GABA is removed from the synaptic cleft by two GABA transporters (GATs), GAT-1 and GAT-3, and their dysfunction affects brain functions. The present study aimed to reveal the ontogeny of the GABA-removal system by examining the immunohistochemical localization of GAT-1 and GAT-3 in the embryonic and postnatal mouse cervical spinal cord. In the dorsal horn, GAT-1 was localized within the presynapses of inhibitory axons after embryonic day 15 (E15), a little prior to GABAergic synapse formation. The GAT-1-positive dots increased in density until postnatal day 21 (P21). By contrast, in the ventral horn, GAT-1-positive dots were sparse during development, although many transient GABAergic synapses were formed before birth. GAT-3 was first localized within the radial processes of radial glia in the ventral part on E12 and the dorsal part on E15. The initial localization of the GAT-3 was almost concomitant with the dispersal of GABAergic neurons. GAT-3 continued to be localized within the processes of astrocytes, and increased in expression until P21. These results suggested the following: (1) before synapse formation, GABA may be transported into the processes of radial glia or immature astrocytes by GAT-3. (2) At the transient GABAergic synapses in the ventral horn, GABA may not be reuptaken into the presynapses. (3) In the dorsal horn, GABA may start to be reuptaken by GAT-1 a little prior to synapse formation. (4) After synapse formation, GAT-3 may continue to remove GABA from immature and mature synaptic clefts into the processes of astrocytes. (5) Development of the GABA-removal system may be completed by P21. PMID:24412234

Kim, J; Kosaka, Y; Shimizu-Okabe, C; Niizaki, A; Takayama, C



GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity.  


We have previously shown that GABA protects pancreatic islet cells against apoptosis and exerts anti-inflammatory effects. Notably, GABA inhibited the activation of NF-?B in both islet cells and lymphocytes. NF-?B activation is detrimental to beta cells by promoting apoptosis. However, the mechanisms by which GABA mediates these effects are unknown. Because the above-mentioned effects mimic the activity of sirtuin 1 (SIRT1) in beta cells, we investigated whether it is involved. SIRT1 is an NAD(+)-dependent deacetylase that enhances insulin secretion, and counteracts inflammatory signals in beta cells. We found that the incubation of a clonal beta-cell line (rat INS-1) with GABA increased the expression of SIRT1, as did GABA receptor agonists acting on either type A or B receptors. NAD(+) (an essential cofactor of SIRT1) was also increased. GABA augmented SIRT1 enzymatic activity, which resulted in deacetylation of the p65 component of NF-?B, and this is known to interfere with the activation this pathway. GABA increased insulin production and reduced drug-induced apoptosis, and these actions were reversed by SIRT1 inhibitors. We examined whether SIRT1 is similarly induced in newly isolated human islet cells. Indeed, GABA increased both NAD(+) and SIRT1 (but not sirtuins 2, 3 and 6). It protected human islet cells against spontaneous apoptosis in culture, and this was negated by a SIRT1 inhibitor. Thus, our findings suggest that major beneficial effects of GABA on beta cells are due to increased SIRT1 and NAD(+), and point to a new pathway for diabetes therapy. PMID:25193706

Prud'homme, Gérald J; Glinka, Yelena; Udovyk, Oleksandr; Hasilo, Craig; Paraskevas, Steven; Wang, Qinghua



Characterization of [(3)H]-CGP54626A binding to heterodimeric GABA(B) receptors stably expressed in mammalian cells.  


Functional human GABA(B(1a,2)) and GABA(B(1b,2)) receptors have been stably expressed in mammalian CHO K1 cells. Detailed characterization of GABA(B) ligand binding at each of the receptors has been compared using [(3)H]-CGP54626A. In cell membranes fractions, [(3)H]-CGP54626A bound to a single site with a K(D) of 1. 51+/-1.12 nM, B(max) of 2.02+/-0.17 pmoles mg protein(-1) and 0. 86+/-0.20 nM, B(max) of 5.19+/-0.57 pmoles mg protein(-1) for GABA(B(1a,2)) and GABA(B(1b,2)) respectively. In competition binding assays the rank order was identical for both GABA(B) receptors. For known GABA(B) agonists the rank order was CGP27492>SKF97541=CGP46381>GABA>Baclofen and for GABA(B) antagonists the rank order was CGP54262A>CGP55845>CGP52432>SCH 50911>CGP51176>CGP36742=CGP35348 > or =2-OH Saclofen > or =ABPA. The allosteric effect of calcium cations was also investigated. The effect of removal of CaCl(2) from the binding assay conditions was ligand dependent to either cause a decrease in ligand affinity or to have no significant effect. However, these effects were similar for both GABA(B) receptors. A whole cell, scintillation proximity binding assay was used to determine agonist affinity at exclusively heterodimeric GABA(B) receptors. In competition assays, the rank order was the same for both GABA(B(1a,2)) and GABA(B(1b,2)) and consistent with that seen with cell membrane fractions. These data suggest that, in terms of ligand binding, the currently identified isoforms of the GABA(B) receptor are pharmacologically indistinguishable. PMID:11139457

Green, A; Walls, S; Wise, A; Green, R H; Martin, A K; Marshall, F H



Transporter-mediated GABA responses in horizontal and bipolar cells of zebrafish retina  

PubMed Central

GABA-mediated interactions between horizontal cells (HCs) and bipolar cells (BCs) transform signals within the image-processing circuitry of distal retina. To further understand this process we have studied the GABA-driven membrane responses from isolated retinal neurons. Papain-dissociated retinal cells from adult zebrafish were exposed to GABAergic ligands while transmembrane potentials were monitored with a fluorescent voltage-sensitive dye (oxonol, DiBaC4(5)). In HCs hyperpolarizing, ionotropic GABA responses were almost never seen, nor were responses to baclofen or glycine. A GABA-induced depolarization followed by after hyperpolarization (dep/AHP) occurred in 38% of HCs. The median fluorescence increase (dep component) was 0.17 log units, about 22 mV. HC dep/AHP was not blocked by bicuculline or picrotoxin. Muscimol rarely evoked dep/AHP responses. In BCs picrotoxin sensitive, hyperpolarizing, ionotropic GABA and muscimol responses occurred in most cells. A picrotoxin insensitive dep/AHP response was seen in about 5% of BCs. The median fluorescence increase (dep component) was 0.18 log units, about 23 mV. Some BCs expressed both muscimol-induced hyperpolarizations and GABA-induced dep/AHP responses. For all cells the pooled Hill fit to median dep amplitudes, in response to treatments with a GABA concentration series, gave an apparent k of 0.61 ?M and an n of 1.1. The dep/AHP responses of all cells required both extracellular Na+ and Cl?, as dep/AHP was blocked reversibly by Li+ substituted for Na+ and irreversibly by isethionate substituted for Cl?. All cells with dep/AHP responses in zebrafish have the membrane physiology of neurons expressing GABA transporters. These cells likely accumulate GABA, a characteristic of GABAergic neurons. We suggest Na+ drives GABA into these cells, depolarizing the plasma membrane and triggering Na+, K+-dependent ATPase. The ATPase activity generates AHP. In addition to a GABA clearance function, these large-amplitude transporter responses may provide an outer plexiform layer GABA sensor mechanism. PMID:18442438

Nelson, Ralph; Bender, Anna M.; Connaughton, Victoria P.



Mesencephalic GABA neuronal development: no more on the other side of oblivion.  


Abstract Midbrain GABA neurons, endowed with multiple morphological, physiological and molecular characteristics as well as projection patterns are key players interacting with diverse regions of the brain and capable of modulating several aspects of behavior. The diversity of these GABA neuronal populations based on their location and function in the dorsal, medial or ventral midbrain has challenged efforts to rapidly uncover their developmental regulation. Here we review recent developments that are beginning to illuminate transcriptional control of GABA neurons in the embryonic midbrain (mesencephalon) and discuss its implications for understanding and treatment of neurological and psychiatric illnesses. PMID:25367618

Li, Suyan; Joshee, Sampada; Vasudevan, Anju



Antidepressants and seizure-interactions at the GABA-receptor chloride-ionophore complex  

SciTech Connect

Convulsive seizures are a potential side effect of antidepressant drug treatment and can be produced by all classes of antidepressants. It is also know that some convulsant and anticonvulsant drug actions are mediated by the GABA-receptor chloride-ionophore complex. Drugs acting at this complex appear to induce convulsions by inhibiting chloride conductance through the associated chloride channel. Using the method of GABA-stimulated /sup 36/Cl-uptake by rat cerebral cortical vesicles, we show that some antidepressant drugs can inhibit the GABA-receptor chloride uptake, and that the degree of chloride channel inhibition by these drugs correlates with the frequency of convulsive seizures induced by them.

Malatynska, E.; Knapp, R.J.; Ikeda, M.; Yamamura, H.I.



Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for ethanol  

Microsoft Academic Search

Long-term exposure to ethanol leads to an imbalance in different excitatory and inhibitory amino acids. When ethanol consumption is reduced or completely stopped, these imbalances in different amino acids and neurotransmitters are behaviorally expressed in the form of ethanol withdrawal. Glutamate, a major excitatory amino acid, and GABA, a major inhibitory amino acid, are responsible, at least partly, for ethanol

Philippe De Witte



Anterior Cingulate Cortex ?-Aminobutyric Acid in Depressed Adolescents  

PubMed Central

Context Anhedonia, a core symptom of major depressive disorder (MDD) and highly variable among adolescents with MDD, may involve alterations in the major inhibitory amino acid neurotransmitter system of ?-aminobutyric acid (GABA). Objective To test whether anterior cingulate cortex (ACC) GABA levels, measured by proton magnetic resonance spectroscopy, are decreased in adolescents with MDD. The associations of GABA alterations with the presence and severity of anhedonia were explored. Design Case-control, cross-sectional study using single-voxel proton magnetic resonance spectroscopy at 3 T. Setting Two clinical research divisions at 2 teaching hospitals. Participants Twenty psychotropic medication-free adolescents with MDD (10 anhedonic, 12 female, aged 12–19 years) with episode duration of 8 weeks or more and 21 control subjects group matched for sex and age. Main Outcome Measures Anterior cingulate cortex GABA levels expressed as ratios relative to unsuppressed voxel tissue water (w) and anhedonia scores expressed as a continuous variable. Results Compared with control subjects, adolescents with MDD had significantly decreased ACC GABA/w (t= 3.2; P<.003). When subjects with MDD were categorized based on the presence of anhedonia, only anhedonic patients had decreased GABA/w levels compared with control subjects (t=4.08; P<.001; PTukey<.001). Anterior cingulate cortex GABA/w levels were negatively correlated with anhedonia scores for the whole MDD group (r = ?0.50; P = .02), as well as for the entire participant sample including the control subjects (r=?0.54; P<.001). Anterior cingulate cortex white matter was also significantly decreased in adolescents with MDD compared with controls (P=.04). Conclusions These findings suggest that GABA, the major inhibitory neurotransmitter in the brain, may be implicated in adolescent MDD and, more specifically, in those with anhedonia. In addition, use of a continuous rather than categorical scale of anhedonia, as in the present study, may permit greater specificity in evaluating this important clinical feature. PMID:21969419

Gabbay, Vilma; Mao, Xiangling; Klein, Rachel G.; Ely, Benjamin A.; Babb, James S.; Panzer, Aviva M.; Alonso, Carmen M.; Shungu, Dikoma C.



Analysis of cerebrospinal fluid ?-aminobutyric acid by capillary electrophoresis with laser-induced fluorescence detection.  


The measurement of ?-aminobutyric acid (GABA) is suitable for investigating various neurological disorders. In this study, a sensitive and selective method for free GABA quantification in cerebrospinal fluid (CSF) has been standardised. This method is based on CE with LIF detection using 4-fluoro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-F) as a derivatisating agent. The reaction conditions (NBD-F concentration, pH, temperature and reaction time) and the electrophoretic parameters (run buffer composition and pH and separation voltage) were optimised to obtain the maximum derivatisation efficiency and electrophoretic resolution. The best resolution was obtained using 200 mM sodium borate, 10 mM SDS, 8.5 mM ?-CD, pH 10 and 20 kV voltage. The method was linear in the concentration range of 2.5-1000 nM with good inter- and intra-assay precision values. The effects of CSF handling on free GABA concentrations were also evaluated. Our results show that the time delay between CSF collection and freezing strongly increases the CSF GABA values. Age-related reference values were established in 55 paediatric controls. The influence of antiepileptic therapy on free CSF GABA was studied in 38 neuropaediatric patients. Significantly, higher GABA values were obtained in patients taking valproic acid or vigabatrin therapy, which are antiepileptic drugs that modulate GABA metabolism. PMID:24338894

Casado, Mercedes; Molero, Marta; Sierra, Cristina; García-Cazorla, Angels; Ormazabal, Aida; Artuch, Rafael



Novel mechanism for presynaptic inhibition: GABA(A) receptors affect the release machinery.  


Presynaptic inhibition is produced by increasing Cl(-) conductance, resulting in an action potential of a smaller amplitude at the excitatory axon terminals. This, in turn, reduces Ca(2+) entry to produce a smaller release. For this mechanism to operate, the "inhibitory" effect of shunting should last during the arrival of the "excitatory" action potential to its terminals, and to achieve that, the inhibitory action potential should precede the excitatory action potential. Using the crayfish neuromuscular preparation which is innervated by one excitatory axon and one inhibitory axon, we found, at 12 degrees C, prominent presynaptic inhibition when the inhibitory action potential followed the excitatory action potential by 1, and even 2, ms. The presynaptic excitatory action potential and the excitatory nerve terminal current (ENTC) were not altered, and Ca(2+) imaging at single release boutons showed that this "late" presynaptic inhibition did not result from a reduction in Ca(2+) entry. Since 50 microM picrotoxin blocked this late component of presynaptic inhibition, we suggest that gamma-aminobutyric acid-A (GABA(A)) receptors reduce transmitter release also by a mechanism other than affecting Ca(2+) entry. PMID:10979998

Parnas, I; Rashkovan, G; Ravin, R; Fischer, Y



Evidence That GABA Mediates Dopaminergic and Serotonergic Pathways Associated with Locomotor Activity in Juvenile Chinook Salmon (Oncorhynchus tshawytscha)  

USGS Publications Warehouse

The authors examined the control of locomotor activity in juvenile salmon (Oncorhynchus tshawytscha) by manipulating 3 neurotransmitter systems-gamma-amino-n-butyric acid (GABA), dopamine, and serotonin-as well as the neuropeptide corticotropin releasing hormone (CRH). Intracerebroventricular (ICV) injections of CRH and the GABAAagonist muscimol stimulated locomotor activity. The effect of muscimol was attenuated by administration of a dopamine receptor antagonist, haloperidol. Conversely, the administration of a dopamine uptake inhibitor (4???,4??? -difluoro-3-alpha-[diphenylmethoxy] tropane hydrochloride [DUI]) potentiated the effect of muscimol. They found no evidence that CRH-induced hyperactivity is mediated by dopaminergic systems following concurrent injections of haloperidol or DUI with CRH. Administration of muscimol either had no effect or attenuated the locomotor response to concurrent injections of CRH and fluoxetine, whereas the GABAA antagonist bicuculline methiodide potentiated the effect of CRH and fluoxetine.

Clements, S.; Schreck, C. B.



Role of medullary GABA signal transduction on parasympathetic reflex vasodilatation in the lower lip.  


In the orofacial area, noxious stimulation of the orofacial structure in the trigeminal region evokes parasympathetic reflex vasodilatation, which occurs via the trigeminal spinal nucleus (Vsp) and the inferior/superior salivatory nucleus (ISN/SSN). However, the neurotransmitter involved in the inhibitory synaptic inputs within these nuclei has never been described. This parasympathetic reflex vasodilatation is suppressed by GABAergic action of volatile anesthetics, such as isoflurane, sevoflurane, and halothane, suggesting that medullary GABAergic mechanism exerts its inhibitory effect on the parasympathetic reflex via an activation of GABA receptors. The aim of the present study was to determine the role of GABA(A) and GABA(B) receptors in the Vsp and the ISN in regulating the lingual nerve (LN)-evoked parasympathetic reflex vasodilatation in the lower lip. Under urethane anesthesia (1g/kg), change in lower lip blood flow elicited by electrical stimulation of the LN was recorded in cervically vago-sympathectomized rats. Microinjection of GABA (10 ?M; 0.3 ?l/site) into the Vsp or the ISN significantly and reversibly attenuated the LN-evoked parasympathetic reflex vasodilatation. Microinjection of the GABA(A) receptor-selective agonist muscimol (100 ?M; 0.3 ?l/site) or the GABA(B) receptor-selective agonist baclofen (100 ?M; 0.3 ?l/site) into the Vsp or the ISN significantly and irreversibly reduced this reflex vasodilatation, and these effects were attenuated by pretreatment with microinjection of each receptor-selective antagonists [GABA(A) receptor selective antagonist bicuculline methiodide (1mM; 0.3 ?l/site) or GABA(B) receptor selective antagonist CGP-35348 (1mM; 0.3 ?l/site)] into the Vsp or the ISN. Microinjection of these antagonists alone into the Vsp or the ISN had no significant effect on this reflex vasodilatation. In addition, microinjection (0.3 ?l/site) of the mixture of muscimol (100 ?M) and baclofen (100 ?M) into the Vsp or the ISN also significantly reduced this reflex vasodilatation. These results suggest that medullary GABA signal transduction inhibits the parasympathetic reflex vasodilatation in the rat lower lip via GABA(A) and GABA(B) receptors in the Vsp and the ISN. PMID:22226507

Kawakami, So; Izumi, Hiroshi; Masaki, Eiji; Kuchiiwa, Satoshi; Mizuta, Kentaro



Tonically active GABA A receptors: modulating gain and maintaining the tone  

Microsoft Academic Search

GABAA receptors not only respond to the local release of GABA from presynaptic terminals, but can also mediate a persistent ‘tonic current’. This reflects the activation of high-affinity GABAA receptors by ambient GABA concentrations. Tonic GABAA-receptor-mediated signalling occurs in different brain regions, shows cell-type-specific differences in magnitude and pharmacology, and changes during brain development. Some clues to the adaptive significance

Alexey Semyanov; Matthew C. Walker; Dimitri M. Kullmann; R. Angus Silver



The effects of volatile anesthetics on synaptic and extrasynaptic GABA-induced neurotransmission.  


Examination of volatile anesthetic actions at single synapses provides more direct information by reducing interference by surrounding tissue and extrasynaptic modulation. We examined how volatile anesthetics modulate GABA release by measuring spontaneous or miniature GABA-induced inhibitory postsynaptic currents (mIPSCs, sIPSCs) or by measuring action potential-evoked IPSCs (eIPSCs) at individual synapses. Halothane increased both the amplitude and frequency of sIPSCs. Isoflurane and enflurane increased mIPSC frequency while sevoflurane had no effect. These anesthetics did not alter mIPSC amplitudes. Halothane increased the amplitude of eIPSCs, with a decrease in failure rate (Rf) and paired-pulse ratio. In contrast, isoflurane and enflurane decreased the eIPSC amplitude and increased Rf, while sevoflurane decreased the eIPSC amplitude without affecting Rf. Volatile anesthetics did not change kinetics except for sevoflurane, suggesting that presynaptic mechanisms dominate changes in neurotransmission. Each anesthetic showed somewhat different GABA-induced response and these results suggest that GABA-induced synaptic transmission cannot have a uniformly common site of action as suggested for volatile anesthetics. In contrast, all volatile anesthetics concentration-dependently enhanced the GABA-induced extrasynaptic currents. Extrasynaptic receptors containing ?4 and ?5 subunits are reported to have high sensitivities to volatile anesthetics. Also, inhibition of GABA uptake by volatile anesthetics results in higher extracellular GABA concentration, which may lead to prolonged activation of extrasynaptic GABAA receptors. The extrasynaptic GABA-induced receptors may be major site of volatile anesthetic-induced neurotransmission. This article is part of a Special Issue entitled 'Extrasynaptic ionotropic receptors'. PMID:22925739

Kotani, Naoki; Akaike, Norio



GABA Neurons in the Ventral Tegmental Area Responding to Peripheral Sensory Input  

PubMed Central

Dopamine (DA) neurons in the ventral tegmental area (VTA) not only participate in reward processing, but also respond to aversive stimuli. Although GABA neurons in this area are actively involved in regulating the firing of DA neurons, few data exist concerning the responses of these neurons to aversive sensory input. In this study, by employing extracellular single-unit recording and spectral analysis techniques in paralyzed and ventilated rats, we found that the firing pattern in 44% (47 of 106) of GABA cells in the VTA was sensitive to the sensory input produced by the ventilation, showing a significant ventilation-associated oscillation in the power spectra. Detailed studies revealed that most ventilation-sensitive GABA neurons (38 of 47) were excited by the stimuli, whereas most ventilation-sensitive DA neurons (11 of 14) were inhibited. When the animals were under anesthesia or the sensory pathways were transected, the ventilation-associated oscillation failed to appear. Systemic administration of non-competitive N-methyl-D-aspartase (NMDA) receptor antagonist MK-801 completely disrupted the association between the firing of GABA neurons and the ventilation. Interestingly, local MK-801 injection into the VTA dramatically enhanced the sensitivity of GABA neurons to the ventilation. Our data demonstrate that both GABA and DA neurons in the VTA can be significantly modulated by sensory input produced by the ventilation, which may indicate potential functional roles of VTA in processing sensation-related input. PMID:23251560

Jin, Guo-Zhang; Zhen, Xuechu



Synthesis of nylon 4 from gamma-aminobutyrate (GABA) produced by recombinant Escherichia coli.  


In this study, we developed recombinant Escherichia coli strains expressing Lactococcus lactis subsp. lactis Il1403 glutamate decarboxylase (GadB) for the production of GABA from glutamate monosodium salt (MSG). Syntheses of GABA from MSG were examined by employing recombinant E. coli XL1-Blue as a whole cell biocatalyst in buffer solution. By increasing the concentration of E. coli XL1-Blue expressing GadB from the OD??? of 2-10, the concentration and conversion yield of GABA produced from 10 g/L of MSG could be increased from 4.3 to 4.8 g/L and from 70 to 78 %, respectively. Furthermore, E. coli XL1-Blue expressing GadB highly concentrated to the OD??? of 100 produced 76.2 g/L of GABA from 200 g/L of MSG with 62.4 % of GABA yield. Finally, nylon 4 could be synthesized by the bulk polymerization using 2-pyrrolidone that was prepared from microbially synthesized GABA by the reaction with Al?O? as catalyst in toluene with the yield of 96 %. PMID:23010721

Park, Si Jae; Kim, Eun Young; Noh, Won; Oh, Young Hoon; Kim, Hye Young; Song, Bong Keun; Cho, Kwang Myung; Hong, Soon Ho; Lee, Seung Hwan; Jegal, Jonggeon



Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis  

PubMed Central

Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors. DOI: PMID:24843012

Tritsch, Nicolas X; Oh, Won-Jong; Gu, Chenghua; Sabatini, Bernardo L



Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis.  


Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors.DOI: PMID:24843012

Tritsch, Nicolas X; Oh, Won-Jong; Gu, Chenghua; Sabatini, Bernardo L



Nutriepigenetic regulation by folate-homocysteine-methionine axis: a review.  


Although normally folic acid is given during pregnancy, presumably to prevent neural tube defects, the mechanisms of this protection are unknown. More importantly it is unclear whether folic acid has other function during development. It is known that folic acid re-methylates homocysteine (Hcy) to methionine by methylene tetrahydrofolate reductase-dependent pathways. Folic acid also generates high-energy phosphates, behaves as an antioxidant and improves nitric oxide (NO) production by endothelial NO synthase. Interestingly, during epigenetic modification, methylation of DNA/RNA generate homocysteine unequivocally. The enhanced overexpression of methyl transferase lead to increased yield of Hcy. The accumulation of Hcy causes vascular dysfunction, reduces perfusion in the muscles thereby causing musculopathy. Another interesting fact is that children with severe hyperhomocysteinaemia (HHcy) have skeletal deformities, and do not live past teenage. HHcy is also associated with the progeria syndrome. Epilepsy is primarily caused by inhibition of gamma-amino-butyric-acid (GABA) receptor, an inhibitory neurotransmitter in the neuronal synapse. Folate deficiency leads to HHcy which then competes with GABA for binding on the GABA receptors. With so many genetic and clinical manifestations associated with folate deficiency, we propose that folate deficiency induces epigenetic alterations in the genes and thereby results in disease. PMID:24213682

Bhargava, Seema; Tyagi, S C



Effect of genetic and pharmacological blockade of GABA receptors on the 5-HT2C receptor function during stress.  


Serotonin (5-HT)2C receptors play a role in psychoaffective disorders and often contribute to the antidepressant and anxiolytic effects of psychotropic drugs. During stress, activation of these receptors exerts a negative feedback on 5-HT release, probably by increasing the activity of GABAergic interneurons. However, to date, the GABA receptor types that mediate the 5-HT2C receptor-induced feedback inhibition are still unknown. To address this question, we assessed the inhibition of 5-HT turnover by a 5-HT2C receptor agonist (RO 60-0175) at the hippocampal level and under conditions of stress, after pharmacological or genetic inactivation of either GABA-A or GABA-B receptors in mice. Neither the GABA-B receptor antagonist phaclofen nor the specific genetic ablation of either GABA-B1a or GABA-B1b subunits altered the inhibitory effect of RO 60-0175, although 5-HT turnover was markedly decreased in GABA-B1a knock-out mice in both basal and stress conditions. In contrast, the 5-HT2C receptor-mediated inhibition of 5-HT turnover was reduced by the GABA-A receptor antagonist bicuculline. However, a significant effect of 5-HT2C receptor activation persisted in mutant mice deficient in the ?3 subunit of GABA-A receptors. It can be inferred that non-?3 subunit-containing GABA-A receptors, but not GABA-B receptors, mediate the 5-HT2C -induced inhibition of stress-induced increase in hippocampal 5-HT turnover in mice. Serotonin (5-HT2C ) receptors expressed by GABA interneurons (2) are known to drive an indirect, GABA-mediated, inhibitory feedback control of 5-HT neurons, especially under stressful conditions. Using mutant mice and selective ligands, we demonstrated that this feedback control involves not only GABA-A receptors (1) but also GABA-B1a receptors (4), that would inhibit the stimulatory influence of cortical glutamatergic afferences (3) on GABA interneurons. Adaptations of these 5-HT-GABA-glu interactions may contribute to the anxiolytic effects of chronic antidepressant treatments. PMID:25113583

Martin, Cédric B P; Gassmann, Martin; Chevarin, Caroline; Hamon, Michel; Rudolph, Uwe; Bettler, Bernhard; Lanfumey, Laurence; Mongeau, Raymond



Development of homospecific activity of GABA-transaminase in the mouse cerebral cortex and cerebellum and in neurons cultured from these brain areas.  


The homospecific activity of GABA-transaminase (EC; GABA-T) in brain or neurons was determined as a function of development in vivo or in culture by measuring the enzyme activity together with the relative amount of GABA-T apoenzyme by the aid of a monospecific anti-GABA-T antibody. It was observed that both in cerebral cortex and cerebellum in vivo and in neurons cultured from these brain regions the homospecific activity of GABA-T changed during development. By incubation of tissue extracts with similar extracts in which GABA-T activity had been selectively and irreversibly destroyed with gamma-vinyl GABA (Vigabatrin) it was established that this change in homospecific activity was at least partly due to the presence of an endogenous activator of GABA-T. The results point towards a rather complex endogenous regulation of GABA-T during development in vivo and in vitro. PMID:2711865

Schousboe, I; Larsson, O M; Schousboe, A



Repeated administration of the GABA B receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats  

Microsoft Academic Search

Rationale  ?-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of central\\u000a reward processes. Acute or chronic administration of GABAB receptor agonists or positive modulators decreased self-administration of various drugs of abuse. Furthermore, GABAB receptor agonists inhibited cue-induced reinstatement of nicotine- and cocaine-seeking behavior. Because of their fewer adverse\\u000a side effects compared with

Styliani Vlachou; Sebastien Guery; Wolfgang Froestl; Deboshri Banerjee; Jessica Benedict; M. G. Finn; Athina Markou



Analysis of Neuroactive Amino Acids Using UHPLC and Electochemical Detection Analysis of Neuroactive Amino Acids Using UHPLC and Electochemical Detection  

Microsoft Academic Search

Amino acids are the essential building blocks of proteins and peptides. They can also take part in intermediary metabolism and act as precur- sors to common biogenic amine neurotransmitters. Certain amino acids act as neurotransmitters and are the major excitatory (aspartate and glutamate) and inhibitory (GABA and taurine) commands in the central nervous system. The measurement of the profile of

Bruce Bailey; Marc Plante; Chris Crafts; Paul Gamache; John Waraska; Ian Acworth


Differential accumulation of ?-aminobutyric acid in elicited cells of two rice cultivars showing contrasting sensitivity to the blast pathogen.  


Intracellular free amino acid pools were quantified in suspension cultured cells of a blast-sensitive and a blast-resistant rice genotype at increasing times after treatment with Magnaporthe oryzae cell wall hydrolysates. Besides some expected variations in free phenylalanine, a remarkable early increase of ?-aminobutyric acid (GABA) levels was evident in both cultivars. Glutamate decarboxylase activity and protein levels were unaffected. GABA homeostasis was recovered in the sensitive cultivar 48 h after the treatment. In contrast, a further GABA accumulation and a general increase of most amino acids was found at this later stage in the resistant genotype, which showed a larger decrease in cell viability as a consequence of elicitor addition. Data support a recently hypothesised role of GABA metabolism in the plant response to fungal pathogens. PMID:24521266

Forlani, G; Bertazzini, M; Giberti, S



Activation kinetics and single channel properties of recombinant alpha1beta2gamma2L GABA(A) receptor channels.  


Recombinant alpha1beta2gamma2L GABA(A) receptor channels, transiently expressed in HEK 293 cells, were investigated using the patch-clamp technique in combination with a device for ultra-fast solution exchange. The dose-response relationship revealed an EC50 of 11.6 +/- 0.9 microM and saturated with 3 mM GABA. The slope between 0.001 and 0.01 mM GABA was 2.2 +/- 0.4, indicating at least three binding sites for GABA. The rise time decreased from about 120 ms at 0.001 mM GABA to about 0.8 ms at 10 mM GABA. Single channel openings were grouped in bursts with an average duration of 10.3 +/- 3.0 ms. More than 95% of the current was represented by a single channel slope conductance of about 29 pS. PMID:9427304

Jahn, K; Hertle, I; Bufler, J; Adelsberger, H; Pestel, E; Zieglgänsberger, W; Dudel, J; Franke, C



Determining the relative efficacy of positive allosteric modulators of the GABAA receptor: design of a screening approach.  


Gamma amino butyric acid receptors (GABA) are major therapeutic targets for the development of drugs in neurological and psychiatric disorders. The new generation of GABAA modulators is targeting subtype selectivity and low/partial efficacy on the receptor to potentially overcome the adverse effects described for drugs with full agonist profile. We evaluated a screening approach to measure the relative efficacy of GABAA positive allosteric modulators (PAM) using automated patch clamp and fluorescence membrane potential assays. We determined that the use of an internal comparator (zolpidem), tested on each cell in parallel to the test compound, provides a reliable approach to measure and compare the relative efficacy of PAM ligands. Patch clamp recordings on recombinant GABAA receptors, using a multiple drug addition protocol, allows us to rank PAM ligands with different levels of efficacies. We observed that fluorescence membrane potential assays are not predictive of the relative efficacies of GABAA PAM ligands. PMID:23989455

Ghisdal, Philippe; Noel, Nadine; Pacico, Nathalie; Martini, Murielle; Foerch, Patrik; Hanon, Etienne; Wolff, Christian



Menthone semicarbazides and thiosemicarbazides as anticonvulsant agents.  


A series of novel (+/-) 3-menthone semi carbazides (1-7) and thiosemicarbazides synthesized using an appropriate synthetic route and characterized by thin layer chromatography and spectral analysis. The anticonvulsant activity of synthesized compounds was established after intraperitoneal administration in three seizure models in mice which include maximal electroshock seizure (MES), subcutaneous pentylene tetrazole (scPTZ) induced seizure and minimal neurotoxicity test. Seven compounds exhibited protection in both models and N(1) - (4-fluorophenyl) - N(4)- (menth-3-one) semicarbazide (4) emerged as the most active compound with MES ED(50) of 44.15mg/kg and scPTZ ED(50) of 38.68mg/kg at 0.25h duration. These compounds were found to elevate gamma-amino butyric acid (GABA) levels in the midbrain region, thus indicating that (+/-) 3-menthone semicarbazides could be considered as a lead molecule in designing of a potent anticonvulsant drug. PMID:20402660

Jain, Jainendra; Kumar, Y; Stables, James; Sinha, Reema



Doubly Selective Multiple Quantum Chemical Shift Imaging and T1 Relaxation Time Measurement of Glutathione (GSH) in the Human Brain In Vivo  

PubMed Central

Mapping of a major antioxidant, glutathione (GSH), was achieved in the human brain in vivo using a doubly selective multiple quantum filtering based chemical shift imaging (CSI) of GSH at 3 T. Both in vivo and phantom tests in CSI and single voxel measurements were consistent with excellent suppression of overlapping signals from creatine, ?-Amino butyric acid (GABA) and macromolecules. The GSH concentration in the fronto-parietal region was 1.20 ± 0.16 µmol/g (mean ± SD, n = 7). The longitudinal relaxation time (T1) of GSH in the human brain was 397 ± 44 ms (mean ± SD, n = 5), which was substantially shorter than those of other metabolites. This GSH CSI method permits us to address regional differences of GSH in the human brain with conditions where oxidative stress has been implicated, including multiple sclerosis, aging and neurodegenerative diseases. PMID:22730142

Choi, In-Young; Lee, Phil



Structures of a ?-aminobutyrate (GABA) transaminase from the s-triazine-degrading organism Arthrobacter aurescens TC1 in complex with PLP and with its external aldimine PLP-GABA adduct.  


Two complex structures of the ?-aminobutyrate (GABA) transaminase A1R958 from Arthrobacter aurescens TC1 are presented. The first, determined to a resolution of 2.80?Å, features the internal aldimine formed by reaction between the ?-amino group of Lys295 and the cofactor pyridoxal phosphate (PLP); the second, determined to a resolution of 2.75?Å, features the external aldimine adduct formed between PLP and GABA in the first half-reaction. This is the first structure of a microbial GABA transaminase in complex with its natural external aldimine and reveals the molecular determinants of GABA binding in this enzyme. PMID:23027742

Bruce, Heather; Nguyen Tuan, Anh; Mangas Sánchez, Juan; Leese, Charlotte; Hopwood, Jennifer; Hyde, Ralph; Hart, Sam; Turkenburg, Johan P; Grogan, Gideon



Glutamate-induced metabolic changes in Lactococcus lactis NCDO 2118 during GABA production: combined transcriptomic and proteomic analysis  

Microsoft Academic Search

GABA is a molecule of increasing nutraceutical interest due to its modulatory activity on the central nervous system and smooth\\u000a muscle relaxation. Potentially probiotic bacteria can produce it by glutamate decarboxylation, but nothing is known about\\u000a the physiological modifications occurring at the microbial level during GABA production. In the present investigation, a GABA-producing\\u000a Lactococcus lactis strain grown in a medium

Roberto Mazzoli; Enrica Pessione; Magali Dufour; Valérie Laroute; Maria Gabriella Giuffrida; Carlo Giunta; Muriel Cocaign-Bousquet; Pascal Loubière



Desensitization of. gamma. -aminobutyric acid receptor from rat brain: two distinguishable receptors on the same membrane  

Microsoft Academic Search

Transmembrane chloride flux mediated by ..gamma..-aminobutyric acid (GABA) receptor can be measured with a mammalian brain homogenate preparation containing sealed membrane vesicles. The preparation can be mixed rapidly with solutions of defined composition. Influx of ³⁶Cl⁻ tracer initiated by mixing with GABA was rapidly terminated by mixing with bicuculline methiodide. The decrease in the isotope influx measurement due to prior

Derek J. Cash; Katragadda Subbarao



Channel opening of. gamma. -aminobutyric acid receptor from rat brain: molecular mechanisms of the receptor responses  

Microsoft Academic Search

The function of ..gamma..-aminobutyric acid (GABA) receptors, which mediate transmembrane chloride flux, can be studied by use of ³⁶Cl⁻ isotope tracer with membrane from mammalian brain by quench-flow technique, with reaction times that allow resolution of the receptor desensitization rates from the ion flux rates. The rates of chloride exchange into the vesicles in the absence and presence of GABA

Derek J. Cash; Katragadda Subbarao



Metabolism of  -aminobutyric acid during cold acclimation and freezing and its relationship to frost tolerance in barley and wheat  

Microsoft Academic Search

Amino acid homeostasis was investigated in frost- resistant barley seedlings under either cold- or freezing- stress conditions. Total free amino acid content varied only slightly, but a substantial conversion of glutamate to c-aminobutyric acid (GABA) was found that was proportional to the severity of the stress. Cold acclimation caused a significant increase in amino acid pools, and induced the expression

Elisabetta Mazzucotelli; Alfredo Tartari; Luigi Cattivelli; Giuseppe Forlani



Extrasynaptic GABAA receptors in mediodorsal thalamic nucleus modulate fear extinction learning  

PubMed Central

Background The gamma-amino-butyric acid (GABA) system is a critical mediator of fear extinction process. GABA can induce “phasic” or “tonic” inhibition in neurons through synaptic or extrasynaptic GABAA receptors, respectively. However, role of the thalamic “tonic GABA inhibition” in cognition has not been explored. We addressed this issue in extinction of conditioned fear in mice. Results Here, we show that GABAA receptors in the mediodorsal thalamic nucleus (MD) modulate fear extinction. Microinjection of gabazine, a GABAA receptor antagonist, into the MD decreased freezing behavior in response to the conditioned stimulus and thus facilitated fear extinction. Interestingly, microinjection of THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), a preferential agonist for the ?-subunit of extrasynaptic GABAA receptors, into the MD attenuated fear extinction. In the opposite direction, an MD-specific knock-out of the extrasynaptic GABAA receptors facilitated fear extinction. Conclusions Our results suggest that “tonic GABA inhibition” mediated by extrasynaptic GABAA receptors in MD neurons, suppresses fear extinction learning. These results raise a possibility that pharmacological control of tonic mode of GABAA receptor activation may be a target for treatment of anxiety disorders like post-traumatic stress disorder. PMID:24886120



?-Aminobutyric acid, acting through ?-aminobutyric acid type A receptors, inhibits the biosynthesis of neurosteroids in the frog hypothalamus  

PubMed Central

Most of the actions of neurosteroids on the central nervous system are mediated through allosteric modulation of the ?-aminobutyric acid type A (GABAA) receptor, but a direct effect of GABA on the regulation of neurosteroid biosynthesis has never been investigated. In the present report, we have attempted to determine whether 3?-hydroxysteroid dehydrogenase (3?-HSD)-containing neurons, which secrete neurosteroids in the frog hypothalamus, also express the GABAA receptor, and we have investigated the effect of GABA on neurosteroid biosynthesis by frog hypothalamic explants. Double immunohistochemical labeling revealed that most 3?-HSD-positive neurons also contain GABAA receptor ?3 and ?2/?3 subunit-like immunoreactivities. Pulse-chase experiments showed that GABA inhibited in a dose-dependent manner the conversion of tritiated pregnenolone into radioactive steroids, including 17-hydroxy-pregnenolone, progesterone, 17-hydroxy-progesterone, dehydroepiandrosterone, and dihydrotestosterone. The effect of GABA on neurosteroid biosynthesis was mimicked by the GABAA receptor agonist muscimol but was not affected by the GABAB receptor agonist baclofen. The selective GABAA receptor antagonists bicuculline and SR95531 reversed the inhibitory effect of GABA on neurosteroid formation. The present results indicate that steroid-producing neurons of the frog hypothalamus express the GABAA receptor ?3 and ?2/?3 subunits. Our data also demonstrate that GABA, acting on GABAA receptors at the hypothalamic level, inhibits the activity of several key steroidogenic enzymes, including 3?-HSD and cytochrome P450C17 (17?-hydroxylase). PMID:11087816

Do-Rego, J. L.; Mensah-Nyagan, G. A.; Beaujean, D.; Vaudry, D.; Sieghart, W.; Luu-The, V.; Pelletier, G.; Vaudry, H.



Analysis of monoamines, adenosine and GABA in tissues of the land snail Helix lucorum and lizard Agama stellio stellio during hibernation.  


The aim of the present study was to determine the levels of monoamines, GABA and adenosine in the brain, heart and haemolymph of the land snail Helix lucorum and in the brain, heart and blood of lizard Agama stellio stellio during long-term hibernation. We measured levels of the monoamines serotonin (5-HT) and its main metabolite 5-hydroxyindole-3-acetic acid (5-HIAA), dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA), norepinephrine (NE) and epinephrine (E). The most abundant amines detected in the brain and heart of active H. lucorum were 5-HT and DA. Of the metabolites examined only 5-HIAA was found in the brain. NE was found at very low levels but only in the brain, while E was not detected in the brain and heart. The levels of 5-HT and 5-HIAA increased in the brain and heart of H. lucorum within the first months of hibernation, showing a significant decrease thereafter. The levels of DA did not change during hibernation. The results indicated that 5-HT might be involved in preparing snails for entry into hibernation. GABA was only found in the brain of H. lucorum, and the levels were low; these levels remained during hibernation. Adenosine was present in brain and heart of H. lucorum, and during hibernation, the level of adenosine decreased significantly in the brain but remained steady in the heart. The monoamines 5-HT, DA and NE were present in the brain of active lizards A. stellio stellio, whereas E was found only at very low levels. Moreover, the metabolites 5-HIAA, DOPAC and HVA were detected in the brain of active lizards. The monoamines 5-HT, DA, NE and E were also detected in the heart and blood of active lizards. During hibernation the levels of these four monoamines were decreased significantly in the brain and heart of A. stellio stellio. In contrast, the levels of E increased in the heart and blood of hibernating lizards. Adenosine was detected in both heart and brain of active lizards, but hibernation caused a marked decrease in its levels at both tissues. GABA was found at higher levels than monoamines and adenosine in the brain of active lizards, and hibernation caused a significant increase in its levels, indicating an important role of GABA in inhibition of neuronal activity in hibernating lizards. PMID:11919272

Michaelidis, Basile; Loumbourdis, Nikolaos S; Kapaki, Elizabeth



In vivo modulation of extracellular hippocampal glutamate and GABA levels and limbic seizures by group I and II metabotropic glutamate receptor ligands.  


The effects of several metabotropic receptor (mGluR) ligands on baseline hippocampal glutamate and GABA overflow in conscious rats and the modulation of limbic seizure activity by these ligands were investigated. Intrahippocampal mGluR group I agonist perfusion via a microdialysis probe [1 mm (R,S)-3,5-dihydroxyphenylglycine] induced seizures and concomitant augmentations in amino acid dialysate levels. The mGlu1a receptor antagonist LY367385 (1 mm) decreased baseline glutamate but not GABA concentrations, suggesting that mGlu1a receptors, which regulate hippocampal glutamate levels, are tonically activated by endogenous glutamate. This decrease in glutamate may contribute to the reported LY367385-mediated anticonvulsant effect. The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (50 mg/kg) also clearly abolished pilocarpine-induced seizures. Agonist-mediated actions at mGlu2/3 receptors by LY379268 (100 microm, 10 mg/kg intraperitoneally) decreased basal hippocampal GABA but not glutamate levels. This may partly explain the increased excitation following systemic LY379268 administration and the lack of complete anticonvulsant protection within our epilepsy model with the mGlu2/3 receptor agonist. Group II selective mGluR receptor blockade with LY341495 (1-10 microm) did not alter the rats' behaviour or hippocampal amino acid levels. These data provide a neurochemical basis for the full anticonvulsant effects of mGlu1a and mGlu5 antagonists and the partial effects observed with mGlu2/3 agonists in vivo. PMID:15009663

Smolders, Ilse; Lindekens, Hilde; Clinckers, Ralph; Meurs, Alfred; O'Neill, Michael J; Lodge, David; Ebinger, Guy; Michotte, Yvette



The effects of volatile anesthetics on the extracellular accumulation of [(3)H]GABA in rat brain cortical slices.  


GABA is an inhibitory neurotransmitter that appears to be associated with the action of volatile anesthetics. These anesthetics potentiate GABA-induced postsynaptic currents by synaptic GABAA receptors, although recent evidence suggests that these agents also significantly affect extrasynaptic GABA receptors. However, the effect of volatile anesthetics on the extracellular concentration of GABA in the central nervous system has not been fully established. In the present study, rat brain cortical slices loaded with [(3)H]GABA were used to investigate the effect of halothane and sevoflurane on the extracellular accumulation of this neurotransmitter. The accumulation of [(3)H]GABA was significantly increased by sevoflurane (0.058, 0.11, 0.23, 0.46, and 0.93 mM) and halothane (0.006, 0.012, 0.024, 0.048, 0072, and 0.096 mM) with an EC50 of 0.26 mM and 35 ?M, respectively. TTX (blocker of voltage-dependent Na(+) channels), EGTA (an extracellular Ca(2+) chelator) and BAPTA-AM (an intracellular Ca(2+) chelator) did not interfere with the accumulation of [(3)H]GABA induced by 0.23 mM sevoflurane and 0.048 mM halothane. SKF 89976A, a GABA transporter type 1 (GAT-1) inhibitor, reduced the sevoflurane- and halothane-induced increase in the accumulation of GABA by 57 and 63 %, respectively. Incubation of brain cortical slices at low temperature (17 °C), a condition that inhibits GAT function and reduces GABA release through reverse transport, reduced the sevoflurane- and halothane-induced increase in the accumulation of [(3)H]GABA by 82 and 75 %, respectively, relative to that at normal temperature (37 °C). Ouabain, a Na(+)/K(+) ATPase pump inhibitor, which is known to induce GABA release through reverse transport, abolished the sevoflurane and halothane effects on the accumulation of [(3)H]GABA. The effect of sevoflurane and halothane did not involve glial transporters because ?-alanine, a blocker of GAT-2 and GAT-3, did not inhibit the effect of the anesthetics. In conclusion, the present study suggests that sevoflurane and halothane increase the accumulation of GABA by inducing the reverse transport of this neurotransmitter. Therefore, volatile anesthetics could interfere with neuronal excitability by increasing the action of GABA on synaptic and extrasynaptic GABA receptors. PMID:24081560

Diniz, Paulo H C; Guatimosim, Cristina; Binda, Nancy S; Costa, Flávia L P; Gomez, Marcus V; Gomez, Renato S



Cortical Gamma-Aminobutyric Acid and Glutamate in Posttraumatic Stress Disorder and Their Relationships to Self-Reported Sleep Quality  

PubMed Central

Study Objectives: To test if posttraumatic stress disorder (PTSD) is associated with low brain gamma-aminobutyric acid (GABA) levels and if reduced GABA is mediated by poor sleep quality. Design: Laboratory study using in vivo proton magnetic resonance spectroscopy (1H MRS) and behavioral testing. Setting: VA Medical Center Research Service, Psychiatry and Radiology. Patients or Participants: Twenty-seven patients with PTSD (PTSD+) and 18 trauma-exposed controls without PTSD (PTSD?), recruited from United States Army reservists, Army National Guard, and mental health clinics. Interventions: None. Measurements and Results: 1H MRS at 4 Tesla yielded spectra from three cortical brain regions. In parieto-occipital and temporal cortices, PTSD+ had lower GABA concentrations than PTSD?. As expected, PTSD+ had higher depressive and anxiety symptom scores and a higher Insomnia Severity Index (ISI) score. Higher ISI correlated with lower GABA and higher glutamate levels in parieto-occipital cortex and tended to correlate with lower GABA in the anterior cingulate. The relationship between parieto-occipital GABA and PTSD diagnosis was fully mediated through insomnia severity. Lower N-acetylaspartate and glutamate concentrations in the anterior cingulate cortex correlated with higher arousal scores, whereas depressive and anxiety symptoms did generally not influence metabolite concentrations. Conclusions: Low brain gamma-aminobutyric acid (GABA) concentration in posttraumatic stress disorder (PTSD) is consistent with most findings in panic and social anxiety disorders. Low GABA associated with poor sleep quality is consistent with the hyperarousal theory of both primary insomnia and PTSD. Our data demonstrate that poor sleep quality mediates low parieto-occipital GABA in PTSD. The findings have implications for PTSD treatment approaches. Citation: 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(5):893-900. PMID:24790267

Meyerhoff, Dieter J.; Mon, Anderson; Metzler, Thomas; Neylan, Thomas C.



?-Aminobutyric Acid Regulates Both the Survival and Replication of Human ?-Cells  

PubMed Central

?-Aminobutyric acid (GABA) has been shown to inhibit apoptosis of rodent ?-cells in vitro. In this study, we show that activation of GABAA receptors (GABAA-Rs) or GABAB-Rs significantly inhibits oxidative stress–related ?-cell apoptosis and preserves pancreatic ?-cells in streptozotocin-rendered hyperglycemic mice. Moreover, treatment with GABA, or a GABAA-R– or GABAB-R–specific agonist, inhibited human ?-cell apoptosis following islet transplantation into NOD/scid mice. Accordingly, activation of GABAA-Rs and/or GABAB-Rs may be a useful adjunct therapy for human islet transplantation. GABA-R agonists also promoted ?-cell replication in hyperglycemic mice. While a number of agents can promote rodent ?-cell replication, most fail to provide similar activities with human ?-cells. In this study, we show that GABA administration promotes ?-cell replication and functional recovery in human islets following implantation into NOD/scid mice. Human ?-cell replication was induced by both GABAA-R and GABAB-R activation. Hence, GABA regulates both the survival and replication of human ?-cells. These actions, together with the anti-inflammatory properties of GABA, suggest that modulation of peripheral GABA-Rs may represent a promising new therapeutic strategy for improving ?-cell survival following human islet transplantation and increasing ?-cells in patients with diabetes. PMID:23995958

Tian, Jide; Dang, Hoa; Chen, Zheying; Guan, Alice; Jin, Yingli; Atkinson, Mark A.; Kaufman, Daniel L.



Decreased left perisylvian GABA concentration in children with autism and unaffected siblings.  


Imbalanced levels of excitation and inhibition (E/I) have been proposed to account for various behavioral and electrophysiological phenotypes in autism. Although proton magnetic resonance spectroscopy ((1)H-MRS) studies have been published on various metabolite levels in autism, including glutamate, the major excitatory neurotransmitter, few (1)H-MRS studies have yet been conducted the major inhibitory neurotransmitter GABA. Seventeen individuals with autism spectrum disorders (ASD) participated in a single-voxel, point resolved spectroscopy (PRESS) study conducted on a 3T magnet. Data were also acquired on 14 unaffected siblings of children with autism, and 17 age- and gender-matched healthy control subjects. GABA concentration was measured along with Creatine (Cr) in a single voxel aligned with the auditory cortex in the perisylvian region of the left hemisphere. The ratio of GABA to Cr was significantly lower in the ASD group than the control subjects. Siblings also exhibited lower GABA/Cr ratios compared to controls. Cr concentration did not differ between groups. The volumes of gray matter, white matter and CSF did not differ between groups in the whole brain or within the spectroscopy voxel. Reduced auditory GABA concentration in ASD is consistent with one previous MRS study of GABA concentration in the frontal lobe in autism, suggesting that multiple neocortical areas may be involved. Lower GABA levels are consistent with theories of ASD as a disorder involving impaired inhibitory neurotransmission and E/I imbalance. The reduction in unaffected siblings suggests that it may be a heritable biomarker, or endophenotype, of autism. PMID:23370056

Rojas, Donald C; Singel, Debra; Steinmetz, Sarah; Hepburn, Susan; Brown, Mark S



Potentiation of pathogen-specific defense mechanisms in Arabidopsis by -aminobutyric acid  

Microsoft Academic Search

The nonprotein amino acids -aminobutyric acid (GABA) and -aminobutyric acid (BABA) have known biological effects in animals and plants. Their mode of action has been the object of thorough research in animals but remains unclear in plants. Our objective was to study the mode of action of BABA in the protection of Arabidopis plants against virulent pathogens. BABA protected Arabidopsis

Laurent Zimmerli; Gabor Jakab; Jean-Pierre Métraux; Brigitte Mauch-Mani



High-resolution autoreactive epitope mapping and structural modeling of the 65 kDa form of human glutamic acid decarboxylase 1 1 Edited by J. A. Wells  

Microsoft Academic Search

The smaller isoform of the GABA-synthesizing enzyme, glutamic acid decarboxylase 65 (GAD65), is unusually susceptible to becoming a target of autoimmunity affecting its major sites of expression, GABA-ergic neurons and pancreatic ?-cells. In contrast, a highly homologous isoform, GAD67, is not an autoantigen. We used homolog-scanning mutagenesis to identify GAD65-specific amino acid residues which form autoreactive B-cell epitopes in this

Heather L. Schwartz; John-Marc Chandonia; Shera F. Kash; Jamil Kanaani; Evelyn Tunnell; Antoinette Domingo; Fred E. Cohen; J. Paul Banga; Anne-Marie Madec; Wiltrud Richter; Steinunn Baekkeskov



Plasticity-related binding of GABA and muscarinic receptor sites in piriform cortex of rat: An autoradiographic study  

SciTech Connect

This study has used the recently developed in vitro quantitative autoradiographic technique to examine the effects of olfactory bulb (OB) removal on receptor-binding sites in the deafferented piriform cortex (PC) of the rat. The gamma-aminobutyric acid-benzodiazepine receptor (GABA-BZR)- and muscarinic cholinergic receptor (MChR)-binding sites in layer I of PC were localized using (3H)flunitrazepam and (3H)quinuclidinyl benzilate as ligands, respectively. From the resultant autoradiograms the optical densities were measured using a Drexel-DUMAS image analysis system. The densities of BZR and MChR-binding sites were markedly increased in the PC ipsilateral to the lesion as compared to the contralateral side in those subjects that were operated in adulthood (Postnatal Day 100, PN 100). Comparisons between the unoperated and PN 100 operated animals also showed significant increases in the deafferented PC. In the animals operated on the day of birth (PN 0) no significant differences were seen between the operated and the contralateral PC. The difference between the PN 0 deafferented PC and the unoperated controls shows a slight decrease in BZR density in the former group; however, in case of the MChR there is a slight increase on the side of the lesion. These results demonstrate that deafferentation of PC by OB removal appears to modulate both the BZR-binding sites that are coupled with the GABA-A receptor complex and the MChR-binding sites. The results also suggest that possibility of a role for these neurotransmitter receptor-binding sites in plasticity following deafferentation.

Thomas, A.P.; Westrum, L.E. (Univ. of Washington, Seattle (USA))



Regulation of GAD expression in rat pancreatic islets and brain by gamma-vinyl-GABA and glucose.  


Glutamic acid decarboxylase (GAD) is an important autoantigen in insulin-dependent diabetes mellitus (IDDM), but little is known about its regulation and function in islet cells. We investigated the effects of the GABA-transaminase inhibitor gamma-vinyl-GABA (GVG) on GAD expression in rat islets and brain in vitro and in vivo. In islets incubated in high glucose culture medium there was an increase in GAD activity, GAD65 and GAD67 protein levels compared to low-glucose conditions; however, even in high glucose, GVG still significantly suppressed GAD activity and GAD67 expression. Our observations suggest that glucose and GVG act on GAD in islets through different mechanisms. Quantitative immunohistochemistry of pancreatic sections from rats treated with GVG in vivo using novel monoclonal antibodies specific for GAD65 and GAD67, showed a decrease in GAD67 expression (p < 0.005) relative to untreated rats. The effects of GVG on rat pancreatic islets were very similar to those observed in brain of rats treated with GVG in vivo. In homogenates of cerebral tissue from GVG treated rats containing both membrane-bound and soluble protein GAD67 levels were significantly decreased while GAD65 levels were not significantly changed compared to untreated rats. In contrast, in homogenates of cerebral tissues containing only soluble cytosolic protein, GVG-treatment was also significantly found to decrease GAD65 levels. Taken together, these results suggest that GVG potentially could be of use to decrease GAD expression in islet cells and consequently to deviate/inhibit the autoimmune response against the beta cells seen in IDDM. PMID:9628269

Petersen, J S; Rimvall, K; Jørgensen, P N; Hasselager, E; Moody, A; Hejnaes, K; Clausen, J T; Dyrberg, T



Conductance increases produced by glycine and gamma-aminobutyric acid in lamprey interneurones.  

PubMed Central

1. Conductances of individual neurones in the isolated lamprey spinal cord were measured with separate intracellular electrodes for recording potentials and for passing current pulses during application of glycine or GABA (0.1-1.0 MM) in Ca-free bathing fluid. Large, reversible increases in conductance were produced in giant interneurones by both amino acids, but Müller axons and sensory dorsal cells were unaffected. 2. Conductance increases produced by glycine and by GABA were selective for Cl. Both conductance increases were linearly related to external Cl concentrations and repeated exposure to the amino acids in Cl-free fluid progressively reduced the conductance increases to less than 1% of their values in normal Cl. 3. Strychnine was a competitive antagonist of glycine, while GABA was antagonized competitively by bicuculline and non-competitively by picrotoxin. 4. The sensitivity of giant interneurones to glycine and GABA increased at low temperatures, in Na-free fluid, and after repeated exposure to the amino acids. Sensitization may have been produced by inhibition of uptake mechanisms for glycine and GABA in the spinal cord. 5. Discharges of interneurones recorded extracellularly were inhibited by bath-applied glycine and GABA, but directly elicited action potentials of axons were unaffected. Strychnine and Cl-free fluid in the presence of Ca produced seizures in lamprey spinal cord. 6. The conclusions of these experiments are that different receptors for glycine and for GABA are present on giant interneurones, that glycine is the better candidate for an inhibitory transmitter in the lamprey spinal cord, and that GABA produces effects similar to those which have been well studied in arthropod muscle. PMID:671350

Homma, S; Rovainen, C M



Methamphetamine-evoked depression of GABAB receptor signaling in GABA neurons of the VTA  

PubMed Central

Psychostimulants induce neuroadaptations in excitatory and fast inhibitory transmission in the ventral tegmental area (VTA). Mechanisms underlying drug-evoked synaptic plasticity of slow inhibitory transmission mediated by GABAB receptors and G protein-gated inwardly rectifying potassium (GIRK/Kir3) channels, however, are poorly understood. Here, we show that one day after methamphetamine (METH) or cocaine exposure, both synaptically-evoked and baclofen-activated GABABR-GIRK currents were significantly depressed in VTA GABA neurons, and remained depressed for 7 days. Presynaptic inhibition mediated by GABABRs on GABA terminals was also weakened. Quantitative immunoelectron microscopy revealed internalization of GABAB1R and GIRK2, which occurred coincident with dephosphorylation of Ser783 in GABAB2R, a site implicated in regulating GABABR surface expression. Inhibition of protein phosphatases recovered GABABR-GIRK currents in VTA GABA neurons of METH-injected mice. This psychostimulant-evoked impairment in GABABR signaling removes an intrinsic brake on GABA neuron spiking, which may augment GABA transmission in the mesocorticolimbic system. PMID:22405207

Padgett, CL; Lalive, AL; Tan, KR; Terunuma, M; Munoz, MB; Pangalos, MN; Martinez-Hernandez, J; Watanabe, M; Moss, SJ; Lujan, R; Luscher, C; Slesinger, PA



Prefrontal/amygdalar system determines stress coping behavior through 5-HT/GABA connection.  


Coping is defined as the behavioral and physiological effort made to master stressful situations. The ability to cope with stress leads either to healthy or to pathogenic outcomes. The medial prefrontal cortex (mpFC) and amygdala are acknowledged as having a major role in stress-related behaviors, and mpFC has a critical role in the regulation of amygdala-mediated arousal in response to emotionally salient stimuli. Prefrontal cortical serotonin (5-hydroxytryptamine (5-HT)) is involved in corticolimbic circuitry, and GABA has a major role in amygdala functioning. Here, using mice, it was assessed whether amygdalar GABA regulation by prefrontal 5-HT is involved in processing stressful experiences and in determining coping outcomes. First (experiment 1), bilateral selective 5-HT depletion in mpFC of mice reduced GABA release induced by stress in basolateral amygdala (BLA) and passive coping in the Forced Swimming Test (FST) (experiment 2). Moreover, prefrontal-amygdala disconnection procedure that combined a selective unilateral 5-HT depletion of mpFC and infusion of an inhibitor of GABA synthesis into the contralateral BLA, thereby to disrupt prefrontal-amygdalar serial connectivity bilaterally, showed that disconnection selectively decreases immobility in the FST. These results point to prefrontal/amygdala connectivity mediated by 5-HT and GABA transmission as a critical neural mechanism in stress-induced behavior. PMID:23636466

Andolina, Diego; Maran, Dario; Valzania, Alessandro; Conversi, David; Puglisi-Allegra, Stefano



Rapid, activity-independent turnover of vesicular transmitter content at a mixed glycine/GABA synapse  

PubMed Central

The release of neurotransmitter via the fusion of transmitter-filled, presynaptic vesicles is the primary means by which neurons relay information. However, little is known regarding the molecular mechanisms that supply neurotransmitter destined for vesicle filling, the endogenous transmitter concentrations inside presynaptic nerve terminals or the dynamics of vesicle refilling after exocytosis. We addressed these issues by recording from synaptically-coupled pairs of glycine/GABA co-releasing interneurons (cartwheel cells) of the mouse dorsal cochlear nucleus. We find that the plasma membrane transporter GlyT2 and the intracellular enzyme glutamate decarboxylase supply the majority of glycine and GABA, respectively. Pharmacological block of GlyT2 or glutamate decarboxylase led to rapid and complete rundown of transmission, whereas increasing GABA synthesis via intracellular glutamate uncaging dramatically potentiated GABA release within one minute. These effects were surprisingly independent of exocytosis, indicating that pre-filled vesicles re-equilibrated upon acute changes in cytosolic transmitter. Titration of cytosolic transmitter with postsynaptic responses indicated that endogenous, non-vesicular glycine/GABA levels in nerve terminals are 5 to 7 mM, and that vesicular transport mechanisms are not saturated under basal conditions. Thus, cytosolic transmitter levels dynamically set the strength of inhibitory synapses in a release-independent manner. PMID:23486948

Apostolides, Pierre F.; Trussell, Laurence O.



Endogenous zinc inhibits GABA(A) receptors in a hippocampal pathway.  


Depending on their subunit composition, GABA(A) receptors can be highly sensitive to Zn(2+). Although a pathological role for Zn(2+)-mediated inhibition of GABA(A) receptors has been postulated, no direct evidence exists that endogenous Zn(2+) can modulate GABAergic signaling in the brain. A possible explanation is that Zn(2+) is mainly localized to a subset of glutamatergic synapses. Hippocampal mossy fibers are unusual in that they are glutamatergic but have also been reported to contain GABA and Zn(2+). Here, we show, using combined Timm's method and post-embedding immunogold, that the same mossy fiber varicosities can contain both GABA and Zn(2+). Chelating Zn(2+) with either calcium-saturated EDTA or N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine had no effect on stratum-radiatum-evoked inhibitory postsynaptic currents (IPSCs), but enhanced IPSCs evoked by stimuli designed to recruit dentate granule cells. We also show that IPSCs recorded in CA3 pyramidal neurons in acute hippocampal slices are depressed by exogenous Zn(2+). This depression was of similar amplitude whether the IPSCs were evoked by stimulation in s. radiatum (to recruit local interneurons) or in the s. granulosum of the dentate gyrus (to recruit mossy fibers). These results show for the first time that GABAergic IPSCs can be modulated by endogenous Zn(2+) and are consistent with GABA release at Zn(2+)-containing mossy fiber synapses. PMID:14561688

Ruiz, Arnaud; Walker, Matthew C; Fabian-Fine, Ruth; Kullmann, Dimitri M



Desensitization mechanism of GABA receptors revealed by single oocyte binding and receptor function.  


Prolonged exposure of most fast neurotransmitter-operated ion channels to agonist drives the receptors into a nonfunctional, or desensitized, state. Despite extensive investigation, desensitization remains a thoroughly characterized, yet poorly understood, process. Part of the difficulty in elucidating the mechanism of desensitization has been an inability to resolve the kinetics of both agonist binding and functional desensitization in the same set of operable receptors. To overcome this limitation, we applied single oocyte 3H-ligand binding and two-electrode voltage clamp to oocytes expressing recombinant alpha1beta2gamma2 GABA receptors. Using this approach, we report several observations fundamental to the mechanism of desensitization. First, we confirm that desensitization reversibly shifts GABA receptors into a high-affinity state. For [3H]GABA binding, the half-maximal binding of the desensitized state was approximately 0.040 microm. Second, we show that, upon agonist removal, this high-affinity state disappears with a time constant of 127 +/- 12 sec (n = 4), similar to the time constant for functional recovery from desensitization of 124 +/- 26 sec (n = 5). [3H]GABA, however, dissociates fourfold faster (tau = 30 +/- 2 sec; n = 3) than functional recovery, indicating that desensitized receptors need not be bound by GABA. These data provide direct evidence for a cyclical model of receptor desensitization. PMID:12223551

Chang, Yongchang; Ghansah, Emmanuel; Chen, Yonghui; Ye, Jiawei; Weiss, David S; Chang, YongChang



Amoxapine inhibition of GABA-stimulated chloride conductance: Investigations of potential sites of activity  

SciTech Connect

Amoxapine inhibits GABA-stimulated chloride conductance by acting on the GABA{sub A}-receptor chloride-ionophore complex which can be studied using membrane vesicles prepared from rat cerebral cortex. Amoxapine produces a right shift in the GABA concentration-response curve for the stimulation of {sup 36}Cl{sup {minus}} uptake into these vesicles with no apparent change in the maximum response. Schild analysis of these data gave a pA{sub 2} value of 5.52 with a slope of 0.79. Amoxapine inhibits the binding of the GABA{sub A} receptor selective antagonist ({sup 3}H)SR 95531 with an IC{sub 50} value of 3.45 {mu}M and a pseudo Hill coefficient of 0.83. In contrast, 10 {mu}M amoxapine inhibits ({sup 3}H) flunitrazepam binding by less than 25% while the benzodiazepine antagonist Ro 15-1788 reduces the amoxapine inhibition of GABA-stimulated chloride conductance only at high concentrations.

Ikeda, M.; Knapp, R.J.; Yamamura, H.I. (Univ. of Arizona, Tucson (USA)); Malatynska, E. (Ohio State Univ., Columbus (USA))



Celecoxib and GABA Cooperatively Prevent the Progression of Pancreatic Cancer In Vitro and in Xenograft Models of Stress-Free and Stress-Exposed Mice  

PubMed Central

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is associated with high levels of psychological distress. We have shown that beta-adrenergic receptors (?-ARs), which are activated by stress neurotransmitters, regulate PDAC cells via cyclic AMP (cAMP)-dependent signaling in vitro, that social stress promotes PDAC progression in mouse xenografts and that ?-aminobutyric acid (GABA) inhibits these responses in vitro and in vivo. The targeted inhibition of stress-induced regulatory pathways may abolish the potentially negative impact of psychological stress on clinical outcomes. Our current data show that chronic exposure of PDAC cell lines Panc-1 (activating point mutations in K-ras) and BXPC-3 (no mutations in K-ras) in vitro to the stress neurotransmitter epinephrine at the concentration (15 nM) previously measured in the serum of mice exposed to social stress significantly increased proliferation and migration. These responses were inhibited in a concentration-dependent manner by celecoxib. The effects of celecoxib alone and in combination with ?-aminobutyric acid (GABA) on the progression of subcutaneous mouse xenografts from the cell line (BXPC-3) most responsive to epinephrine were then investigated in the presence and absence of social stress. Cancer-stimulating factors (VEGF & prostaglandin E2 [PGE2]) and levels of cAMP were measured by immunoassays in blood and xenograft tissue. Phosphorylation of the signaling proteins ERK, CREB, Src, and AKT was assessed by ELISA assays and Western blotting. Expression of COX-2, 5-lipoxygenase, and p-5-LOX were determined by semi-quantitative Western blotting. Celecoxib alone significantly inhibited xenograft progression and decreased systemic and tumor VEGF, PGE2, and cAMP as well as phosphorylated signaling proteins in stress-exposed and stress-free mice. These responses were significantly enhanced by co-treatment with GABA. The celecoxib-induced downregulation of COX-2 protein and p-5-LOX was also significantly enhanced by GABA under both experimental conditions. Our findings identify the targeted inhibition of stress-induced pathways as a promising area for more effective cancer intervention in pancreatic cancer. PMID:22916251

Al-Wadei, Hussein A. N.; Al-Wadei, Mohammed H.; Ullah, Mohammad F.; Schuller, Hildegard M.



Genetic association of recovery from eating disorders: the role of GABA receptor SNPs.  


Follow-up studies of eating disorders (EDs) suggest outcomes ranging from recovery to chronic illness or death, but predictors of outcome have not been consistently identified. We tested 5151 single-nucleotide polymorphisms (SNPs) in approximately 350 candidate genes for association with recovery from ED in 1878 women. Initial analyses focused on a strictly defined discovery cohort of women who were over age 25 years, carried a lifetime diagnosis of an ED, and for whom data were available regarding the presence (n=361 ongoing symptoms in the past year, ie, 'ill') or absence (n=115 no symptoms in the past year, ie, 'recovered') of ED symptoms. An intronic SNP (rs17536211) in GABRG1 showed the strongest statistical evidence of association (p=4.63 × 10(-6), false discovery rate (FDR)=0.021, odds ratio (OR)=0.46). We replicated these findings in a more liberally defined cohort of women age 25 years or younger (n=464 ill, n=107 recovered; p=0.0336, OR=0.68; combined sample p=4.57 × 10(-6), FDR=0.0049, OR=0.55). Enrichment analyses revealed that GABA (?-aminobutyric acid) SNPs were over-represented among SNPs associated at p<0.05 in both the discovery (Z=3.64, p=0.0003) and combined cohorts (Z=2.07, p=0.0388). In follow-up phenomic association analyses with a third independent cohort (n=154 ED cases, n=677 controls), rs17536211 was associated with trait anxiety (p=0.049), suggesting a possible mechanism through which this variant may influence ED outcome. These findings could provide new insights into the development of more effective interventions for the most treatment-resistant patients. PMID:21750581

Bloss, Cinnamon S; Berrettini, Wade; Bergen, Andrew W; Magistretti, Pierre; Duvvuri, Vikas; Strober, Michael; Brandt, Harry; Crawford, Steve; Crow, Scott; Fichter, Manfred M; Halmi, Katherine A; Johnson, Craig; Kaplan, Allan S; Keel, Pamela; Klump, Kelly L; Mitchell, James; Treasure, Janet; Woodside, D Blake; Marzola, Enrica; Schork, Nicholas J; Kaye, Walter H



Oligodendroglial and astroglial heterogeneity in mouse primary central nervous system culture as demonstrated by differences in GABA and D-aspartate transport and immunocytochemistry.  


Using simultaneous autoradiography and immunofluorescence we have investigated the functional heterogeneity amongst oligodendrocytes and astrocytes in primary mouse central nervous system (CNS) culture as expressed by differences in their ability to accumulate gamma-[3H]aminobutyric acid [( 3H]GABA) and D-[3H]aspartate. We have used a range of specific antibodies that identify oligodendrocytes and astrocytes, from precursor to fully mature cells, to address the question of whether all neuroglial cells are capable of expressing this function. Our results showing that A2B5-, 03-, and galactocerebroside-positive cells became heavily labelled with these two neuroactive amino acids, whereas cells expressing the myelin proteins 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) and myelin basic protein (MBP) did not, demonstrate that this capacity is already present in oligodendrocytes at early developmental stages but may not extend to fully mature cells. Astrocytes in culture exhibited a large degree of variability with respect to their ability to transport GABA and D-aspartate. When grown in either serum-containing or serum-free hormone supplemented culture medium two morphologically distinct of glial fibrillary acidic protein (GFAP)-positive astrocyte were identified, process-bearing and epithelioid. Process-bearing cells became heavily labelled with the amino acids under both growth conditions, whereas, data showed that although epithelioid astrocytes were not, or only lightly, labelled with either amino acid in serum-containing cultures, when grown in serum-free culture medium they became more heavily labelled. Thus the expression, in culture, by epithelioid astrocytes, of one of the functions attributed to these cells is largely dependent on growth conditions. PMID:3315124

Reynolds, R; Herschkowitz, N



Tonic GABA(A) receptor-mediated currents in human brain.  


GABA(A) receptors can mediate both phasic (synaptic) and tonic (extrasynaptic) forms of inhibition. It has been proposed that tonic inhibition plays a critical part in controlling neuronal and network excitability. Although tonic GABA(A) receptor-mediated currents have been well characterized in rodents, their existence in human tissue has yet to be demonstrated. Here we show that tonic currents can be recorded from human tissue obtained from patients undergoing temporal lobectomies. Tonic GABA(A) receptor-mediated currents were present in pyramidal cells and interneurons in layer V-VI of temporal neocortex and granule cells in the dentate gyrus. These tonic currents have cell type-specific pharmacologies, opening up the possibility of targeted therapeutics. PMID:16930441

Scimemi, Annalisa; Andersson, Anna; Heeroma, Joost H; Strandberg, Joakim; Rydenhag, Bertil; McEvoy, Andrew W; Thom, Maria; Asztely, Fredrik; Walker, Matthew C



Effects of GABA on neuronal activities in the distal retina of the carp.  


When a transient depolarization was evoked in horizontal cells by a transretinal current pulse, a small hyperpolarizing deflection (probably IPSP) was detected in cones. The IPSP was abolished by superfusion of the retina with GABA-containing Ringer solution, which also hyperpolarized the cones. These results suggest that, in the dark, a GABA-mediated negative feedback was operating from horizontal cells to cones, and terminated in the light. Application of GABA also caused remarkable changes in spectral response curves of horizontal cells, mainly because of suppression of responses to monochromatic lights of longer wavelengths. Therefore, it was concluded that the feedback plays an important role in mechanisms of conversion from the trichromatic process in cones to the opponent color process in horizontal cells. PMID:755289

Murakami, M; Shimoda, Y; Nakatani, K



The GABA B agonist baclofen reduces cigarette consumption in a preliminary double-blind placebo-controlled smoking reduction study  

Microsoft Academic Search

The surge in dopamine in ventral striatal regions in response to drugs of abuse and drug-associated stimuli is a final common pathway of addiction processes. GABA B agonists exert their effects indirectly, by quieting dopaminergic afferents. The ability of the GABA B agonist, baclofen to ameliorate nicotine and drug motivated behavior is established within the animal literature, however its potential

Teresa R. Franklin; Derek Harper; Kyle Kampman; Susan Kildea-McCrea; Will Jens; Kevin G. Lynch; Charles P. O’Brien; Anna Rose Childress



Rundown of GABA type A receptors is a dysfunction associated with human drug-resistant mesial temporal lobe epilepsy.  


Pharmacotherapeutic strategies have been difficult to develop for several forms of temporal lobe epilepsy, which are consequently treated by surgical resection. To examine this problem, we have studied the properties of transmitter receptors of tissues removed during surgical treatment. We find that when cell membranes, isolated from the temporal neocortex of patients afflicted with drug-resistant mesial temporal lobe epilepsy (TLE), are injected into frog oocytes they acquire GABA type A receptors (GABA(A)-receptors) that display a marked rundown during repetitive applications of GABA. In contrast, GABA(A)-receptor function is stable in oocytes injected with cell membranes isolated from the temporal lobe of TLE patients afflicted with neoplastic, dysgenetic, traumatic, or ischemic temporal lesions (lesional TLE, LTLE). Use-dependent GABA(A)-receptor rundown is also found in the pyramidal neurons of TLE neocortical slices and is antagonized by BDNF. Pyramidal neurons in cortical slices of a traumatic LTLE patient did not show GABA(A)-receptor rundown. However, the apparent affinity of GABA(A)-receptor in oocytes microtransplanted with membranes from all of the epileptic patients studied was smaller than the affinity of receptors transplanted from the nonepileptic brain. We conclude that the use-dependent rundown of neocortical GABA(A)-receptor represents a TLE-specific dysfunction, whereas the reduced affinity may be a general feature of brains of both TLE and LTLE patients, and we speculate that our findings may help to develop new treatments for TLE and LTLE. PMID:16217016

Ragozzino, D; Palma, E; Di Angelantonio, S; Amici, M; Mascia, A; Arcella, A; Giangaspero, F; Cantore, G; Di Gennaro, G; Manfredi, M; Esposito, V; Quarato, P P; Miledi, R; Eusebi, F



Sequential Release of GABA by Exocytosis and Reversed Uptake Leads to Neuronal Swelling in Simulated Ischemia of Hippocampal Slices  

Microsoft Academic Search

GABA release during cerebral energy deprivation (produced by anoxia or ischemia) has been suggested either to be neuroprotective, because GABA will hyperpolarize neurons and reduce release of excitotoxic glutamate, or to be neurotoxic, because activation of GABAA receptors facilitates Cl entry into neurons and consequent cell swelling. We have used the GABAA receptors of hippocampal area CA1 pyramidal cells to

Nicola J. Allen; David J. Rossi; David Attwell



Effects of the volatile anesthetic enflurane on spontaneous discharge rate and GABA(A)-mediated inhibition of Purkinje cells in rat cerebellar slices.  


The effects of the volatile anesthetic enflurane on the spontaneous action potential firing and on gamma-aminobutyric acid-A (GABA(A))-mediated synaptic inhibition of Purkinje cells were investigated in sagittal cerebellar slices. The anesthetic shifted the discharge patterns from continuous spiking toward burst firing and decreased the frequency of extracellularly recorded spontaneous action potentials in a concentration-dependent manner. Half-maximal reduction was observed at a concentration corresponding to 2 MAC (1 MAC induces general anesthesia in 50% of patients and rats). When the GABA(A) antagonist bicuculline was present, 2 MAC enflurane reduced action potential firing only by 13 +/- 8% (mean +/- SE). In further experiments, inhibitory postsynaptic currents (IPSCs) were monitored in the whole cell patch-clamp configuration from cells voltage clamped close to -80 mV. At 1 MAC, enflurane attenuated the mean amplitude of IPSCs by 54 +/- 3% while simultaneously prolonging the time courses of monoexponential current decays by 413 +/- 69%. These effects were similar when presynaptic action potentials were suppressed by 1 microM tetrodotoxin. At 1-2 MAC, enflurane increased GABA(A)-mediated inhibition of Purkinje cells by 97 +/- 20% to 159 +/- 38%. During current-clamp recordings, the anesthetic (2 MAC) hyperpolarized the membrane potential by 5.2 +/- 1.1 mV in the absence, but only by 1.6 +/- 1.2 mV in the presence, of bicuculline. These results suggest that enflurane-induced membrane hyperpolarizations, as well as the reduction of spike rates, were partly caused by an increase in synaptic inhibition. Induction of burst firing was related to other actions of the anesthetic, probably an accelerated activation of an inwardly directed cationic current and a depression of spike afterhyperpolarizations. PMID:9163374

Antkowiak, B; Heck, D



Reduced Insular ?-Aminobutyric Acid in Fibromyalgia  

PubMed Central

Objective Recent scientific findings have reinvigorated interest in examining the role of ?-aminobutyric acid (GABA), the major inhibitory central nervous system neurotransmitter, in chronic pain conditions. Decreased inhibitory neurotransmission is a proposed mechanism in the pathophysiology of chronic pain syndromes such as fibromyalgia (FM). The purpose of this study was to test the hypothesis that decreased levels of insular and anterior cingulate GABA would be present in FM patients, and that the concentration of this neurotransmitter would be correlated with pressure–pain thresholds. Methods Sixteen FM patients and 17 age- and sex-matched healthy controls underwent pressure–pain testing and a 3T proton magnetic resonance spectroscopy session in which the right anterior insula, right posterior insula, anterior cingulate, and occipital cortex were examined in subjects at rest. Results GABA levels in the right anterior insula were significantly lower in FM patients compared with healthy controls (mean ± SD 1.17 ± 0.24 arbitrary institutional units versus 1.42 ± 0.32 arbitrary institutional units; P = 0.016). There was a trend toward increased GABA levels in the anterior cingulate of FM patients compared with healthy controls (P = 0.06). No significant differences between groups were detected in the posterior insula or occipital cortex (P > 0.05 for all comparisons). Within the right posterior insula, higher levels of GABA were positively correlated with pressure–pain thresholds in the FM patients (Spearman's rho = 0.63; P = 0.02). Conclusion Diminished inhibitory neurotransmission resulting from lower concentrations of GABA within the right anterior insula may play a role in the pathophysiology of FM and other central pain syndromes. PMID:21913179

Foerster, Bradley R.; Petrou, Myria; Edden, Richard A. E.; Sundgren, Pia C.; Schmidt-Wilcke, Tobias; Lowe, Suzan E.; Harte, Steven E.; Clauw, Daniel J.; Harris, Richard E.



Contribution of ventral tegmental GABA receptors to cocaine self-administration in rats  

PubMed Central

Recent evidence has suggested that compounds affecting GABAergic transmission may provide useful pharmacological tools for the treatment of cocaine addiction. Using a rat model of self-administration, the present study examined the effects of GABA agonists and antagonists injected directly into the ventral tegmental area (VTA) on cocaine intake in rats trained to self-administer cocaine (0, 125, 250 and 500 µg/infusion) under an FR5 schedule of reinforcement. Separate groups of rats received bilateral intra-VTA injections of the GABA-A antagonist picrotoxin (34 ng/side, n=7; 68 ng/side, n=8), GABA-A agonist muscimol (14 ng/side, n=8), GABA-B agonist baclofen (56 ng/side, n=7; 100 ng/side, n=6), picrotoxin (68 ng/side) co-injected with the GABA-B antagonist 2-hydroxysaclofen (100 ng/side, n=7; 2 µg/side, n=8) or artificial cerebrospinal fluid (aCSF, n=6) to assess the effects of the various compounds on the cocaine self-administration dose-response curve. Both picrotoxin and baclofen reduced responding maintained by cocaine, whereas muscimol had no effect on responding. In contrast, neither picrotoxin (n=6) nor baclofen (n=8) affected responding maintained by food. Interestingly, 2-hydroxysaclofen effectively blocked the suppression of responding produced by picrotoxin, suggesting that both picrotoxin and baclofen exert their effects via activation of GABA-B receptors. Additionally, these effects appear to be specific to cocaine reinforcement, supporting current investigation of baclofen as a treatment for cocaine addiction. PMID:17943439

Backes, E.N.; Hemby, S.E.



GABA and glutamate in schizophrenia: A 7 T 1H-MRS study  

PubMed Central

Schizophrenia is characterized by loss of brain volume, which may represent an ongoing pathophysiological process. This loss of brain volume may be explained by reduced neuropil rather than neuronal loss, suggesting abnormal synaptic plasticity and cortical microcircuitry. A possible mechanism is hypofunction of the NMDA-type of glutamate receptor, which reduces the excitation of inhibitory GABAergic interneurons, resulting in a disinhibition of glutamatergic pyramidal neurons. Disinhibition of pyramidal cells may result in excessive stimulation by glutamate, which in turn could cause neuronal damage or death through excitotoxicity. In this study, GABA/creatine ratios, and glutamate, NAA, creatine and choline concentrations in the prefrontal and parieto-occipital cortices were measured in 17 patients with schizophrenia and 23 healthy controls using proton magnetic resonance spectroscopy at an ultra-high magnetic field strength of 7 T. Significantly lower GABA/Cr ratios were found in patients with schizophrenia in the prefrontal cortex as compared to healthy controls, with GABA/Cr ratios inversely correlated with cognitive functioning in the patients. No significant change in the GABA/Cr ratio was found between patients and controls in the parieto-occipital cortex, nor were levels of glutamate, NAA, creatine, and choline differed in patients and controls in the prefrontal and parieto-occipital cortices. Our findings support a mechanism involving altered GABA levels distinguished from glutamate levels in the medial prefrontal cortex in schizophrenia, particularly in high functioning patients. A (compensatory) role for GABA through altered inhibitory neurotransmission in the prefrontal cortex may be ongoing in (higher functioning) patients with schizophrenia. PMID:25379453

Marsman, Anouk; Mandl, Rene C.W.; Klomp, Dennis W.J.; Bohlken, Marc M.; Boer, Vincent O.; Andreychenko, Anna; Cahn, Wiepke; Kahn, Rene S.; Luijten, Peter R.; Hulshoff Pol, Hilleke E.



Dynamic modulation of an orientation preference map by GABA responsible for age-related cognitive performance.  


Accumulating evidence suggests that cognitive declines in old (healthy) animals could arise from depression of intracortical inhibition, for which a decreased ability to produce GABA during senescence might be responsible. By simulating a neural network model of a primary visual cortical (V1) area, we investigated whether and how a lack of GABA affects cognitive performance of the network: detection of the orientation of a visual bar-stimulus. The network was composed of pyramidal (P) cells and GABAergic interneurons such as small (S) and large (L) basket cells. Intrasynaptic GABA-release from presynaptic S or L cells contributed to reducing ongoing-spontaneous (background) neuronal activity in a different manner. Namely, the former exerted feedback (S-to-P) inhibition and reduced the frequency (firing rate) of action potentials evoked in P cells. The latter reduced the number of saliently firing P cells through lateral (L-to-P) inhibition. Non-vesicular GABA-release, presumably from glia and/or neurons, into the extracellular space reduced the both, activating extrasynaptic GABAa receptors and providing P cells with tonic inhibitory currents. By this combinatorial, spatiotemporal inhibitory mechanism, the background activity as noise was significantly reduced, compared to the stimulus-evoked activity as signal, thereby improving signal-to-noise (S/N) ratio. Interestingly, GABA-spillover from the intrasynaptic cleft into the extracellular space was effective for improving orientation selectivity (orientation bias), especially when distractors interfered with detecting the bar-stimulus. These simulation results may provide some insight into how the depression of intracortical inhibition due to a reduction in GABA content in the brain leads to age-related cognitive decline. PMID:22990592

Miyamoto, Ai; Hasegawa, Jun; Hoshino, Osamu



Structural mechanisms underlying benzodiazepine modulation of the GABA(A) receptor.  


Many clinically important drugs target ligand-gated ion channels; however, the mechanisms by which these drugs modulate channel function remain elusive. Benzodiazepines (BZDs), anesthetics, and barbiturates exert their CNS actions by binding to GABA(A) receptors and modulating their function. The structural mechanisms by which BZD binding is transduced to potentiation or inhibition of GABA-induced current (I(GABA)) are essentially unknown. Here, we explored the role of the gamma(2)Q182-R197 region (Loop F/9) in the modulation of I(GABA) by positive (flurazepam, zolpidem) and negative [3-carbomethoxy-4-ethyl-6,7-dimethoxy-beta-carboline (DMCM)] BZD ligands. Each residue was individually mutated to cysteine, coexpressed with wild-type alpha(1) and beta(2) subunits in Xenopus oocytes, and analyzed using two-electrode voltage clamp. Individual mutations differentially affected BZD modulation of I(GABA). Mutations affecting positive modulation span the length of this region, whereas gamma(2)W183C at the beginning of Loop F was the only mutation that adversely affected DMCM inhibition. Radioligand binding experiments demonstrate that mutations in this region do not alter BZD binding, indicating that the observed changes in modulation result from changes in BZD efficacy. Flurazepam and zolpidem significantly slowed covalent modification of gamma(2)R197C, whereas DMCM, GABA, and the allosteric modulator pentobarbital had no effects, demonstrating that gamma(2)Loop F is a specific transducer of positive BZD modulator binding. Therefore, gamma(2)Loop F plays a key role in defining BZD efficacy and is part of the allosteric pathway allowing positive BZD modulator-induced structural changes at the BZD binding site to propagate through the protein to the channel domain. PMID:18367615

Hanson, Susan M; Czajkowski, Cynthia



Serotonin-GABA interactions modulate MDMA-induced mesolimbic dopamine release.  


3,4,-Methylenedioxymethamphetamine (MDMA; 'ecstasy') acts at monoamine nerve terminals to alter the release and re-uptake of dopamine and 5-HT. The present study used microdialysis in awake rats to measure MDMA-induced changes in extracellular GABA in the ventral tegmental area (VTA), simultaneous with measures of extracellular dopamine (DA) in the nucleus accumbens (NAC) shell. (+)-MDMA (0, 2.5, 5 and 10 mg/kg, i.p.) increased GABA efflux in the VTA with a bell-shaped dose-response. This increase was blocked by application of TTX through the VTA probe. MDMA (5 mg/kg) increased 5-HT efflux in VTA by 1037% (p < 0.05). The local perfusion of the 5-HT(2B/2C) antagonist SB 206553 into the VTA reduced VTA GABA efflux after MDMA from a maximum of 229% to a maximum of 126% of basal values (p < 0.05), while having no effect on basal extracellular GABA concentrations. DA concentrations measured simultaneously in the NAC shell were increased from a maximum of 486% to 1320% (p < 0.05). The selective DA releaser d-amphetamine (AMPH) (4 mg/kg) also increased VTA GABA efflux (180%), did not alter 5-HT and increased NAC DA (875%) (p < 0.05), but the perfusion of SB 206553 into the VTA failed to alter these effects. These results suggest that MDMA-mediated increases in DA within the NAC shell are dampened by increases in VTA GABA subsequent to activation of 5-HT(2B/2C) receptors in the VTA. PMID:15525339

Bankson, Michael G; Yamamoto, Bryan K



Activation of neurokinin-1 receptors promotes GABA release at synapses in the rat entorhinal cortex.  


We have previously shown that activation of neurokinin-1 receptors reduces acutely provoked epileptiform activity in rat entorhinal cortex in vitro, and suggested that this may result from an increase in GABA release from inhibitory interneurones. In the present study we have made whole cell patch clamp recordings of spontaneous GABA-mediated inhibitory postsynaptic currents as an indicator of GABA release in slices of rat entorhinal cortex, and determined the effects of neurokinin receptor activation on this release. The neurokinin-1 receptor agonists septide and GR73632 provoked a robust increase in the frequency of GABA-mediated currents, and an increase in mean amplitude. The effects were mimicked by substance P, and blocked by a neurokinin-1 receptor antagonist. High concentrations of neurokinin A had similar effects, which were also blocked by the neurokinin-1 receptor antagonist, but agonists at neurokinin-2 or neurokinin-3 receptors were ineffective. The increases in amplitude and frequency of events provoked by septide were prevented by prior blockade of action potential-dependent release with tetrodotoxin. In current clamp recordings from putative interneurones, GR73632 evoked depolarisation and a prolonged discharge of action potentials. Finally, recordings from pyramidal neurones and oriens-alveus interneurones in CA1 of the hippocampus showed that application of GR73632 caused an increase in frequency and amplitude of GABA-mediated inhibitory postsynaptic currents in the former and persistent firing of action potentials in the latter. The results demonstrate that neurokinin-1 receptor activation promotes the release of GABA at synapses on principal neurones in both entorhinal cortex and hippocampus. The abolition of this effect by tetrodotoxin and the excitatory responses seen in interneurones clearly suggest that the neurokinin-1 receptor is localised on the soma-dendritic domain of the inhibitory neurones. Thus, substance P inputs to inhibitory neurones may have a widespread influence on cortical network excitability and could play a role in epileptogenesis and its control. PMID:12421623

Stacey, A E; Woodhall, G L; Jones, R S G



Amino Acid Neurotransmitters Assessed by 1H MRS: Relationship to Treatment-Resistance in Major Depressive Disorder  

PubMed Central

Background Significant alterations in ?-aminobutyric acid (GABA) and glutamate levels have been previously reported in symptomatic and remitted major depressive disorder (MDD); however, no studies to date have investigated potential associations between these amino acid neurotransmitters and treatment-resistance. Methods The objective of this study was to compare occipital cortex (OCC) and anterior cingulate cortex (ACC) GABA and glutamate+glutamine (“Glx”) levels measured in vivo by proton magnetic resonance spectroscopy (1H MRS) in 15 medication-free treatment-resistant depression (TRD) patients with those in 18 non-treatment-resistant MDD (nTRD) patients and 24 healthy volunteers (HVs). Results Levels of OCC GABA relative to voxel tissue water (W) were decreased in TRD patients compared to both HV (20.2% mean reduction; p=.001; Cohen’s d=1.3) and nTRD subjects (16.4% mean reduction; p=.007; Cohen’s d=1.4). There was a similar main effect of diagnosis for ACC GABA/W levels (p=.047; Cohen’s d=0.76) with TRD patients exhibiting reduced GABA in comparison to the other two groups (22.4–24.5% mean reductions). Group differences in Glx/W were not significant in either brain region in primary ANOVA analyses. Only GABA results in OCC survived correction for multiple comparisons. Conclusions Our findings corroborate previous reports of decreased GABA in MDD and provide initial evidence for a distinct neuronal amino acid profile in patients who have failed to respond to several standard antidepressants, possibly indicative of abnormal glutamate/glutamine/GABA cycling. Given interest in novel antidepressant mechanisms in TRD that selectively target amino acid neurotransmitter function, the translational relevance of these findings awaits further study. PMID:19058788

Price, Rebecca B.; Shungu, Dikoma C.; Mao, Xiangling; Nestadt, Paul; Kelly, Chris; Collins, Katherine A.; Murrough, James W.; Charney, Dennis S.; Mathew, Sanjay J.



GABA, progesterone and zona pellucida activation of PLA2 and regulation by MEK-ERK1/2 during acrosomal exocytosis  

E-print Network

GABA, progesterone and zona pellucida activation of PLA2 and regulation by MEK-ERK1/2 during Nebreda Abstract We investigated whether GABA activates phospholi- pase A2 (PLA2) during acrosomal exocytosis, and if the MEK- ERK1/2 pathway modulates PLA2 activation initiated by GABA, progesterone or zona

Museo Nacional de Ciencias Naturales


[Neurotrophic action of nicotinamide and nicotinoyl-GABA in rat brain in experimental Parkinsonism].  


It was established, that the content of nicotinamide adenine dinucleotides and the binding of NAD by isolated brain cortex synaptic membranes under experimental parkinsonism are impaired. Treatment of the experimental results in the Scatchard plots for binding of [U-14C]NAD to the brain cortex synaptic membranes demonstrated that binding capacities lowered, without changes of affinities. NAD-glycohydrolase involved in development of this pathology. The modulative effect of in vivo administered NAm and nicotinoyl-GABA supposes that NAm acts via NAD which binds specifically with synaptic membranes. Thus, NAm and nicotinoyl-GABA are involved in the regulation of the processes in the brain under experimental parkinsonism. PMID:10402661

Kuchmerovs'ka, T M



Hippocampal Betaine/GABA Transporter mRNA Expression is not Regulated by Inflammation or Dehydration Post-Status Epilepticus  

PubMed Central

Seizure activity can alter GABA transporter and osmoprotective gene expression, which may be involved in the pathogenesis of epilepsy. However, the response of the betaine/GABA transporter is unknown. The goal of the present study was to compare the expression of betaine/GABA transporter mRNA to that of other osmoprotective genes and GABA transporters following status epilepticus (SE). The possible contributory role of dehydration and inflammation was also investigated because both have been shown to be involved in the regulation of GABA transporter and/or osmoprotective gene expression. BGT1 mRNA was increased 24 h post-SE, as were osmoprotective genes. BGT1 was decreased 72 h and 4 weeks post-SE, as were the GABA transporter mRNAs. The mRNA values for osmoprotective genes following 24-hour water withdrawal were significantly lower than the values obtained 24 h post-SE despite similarities in their plasma osmolality values. Betaine/GABA transporter mRNA was not altered by lipopolysaccharide-induced inflammation while the transcription factor TonEBP and the GABA transporters (GAT1 and 3) were. These results suggest that neither plasma osmolality nor inflammation fully account for the changes seen in betaine/GABA transporter mRNA expression post-SE. However, it is evident that BGT1 mRNA expression is altered by SE and displays a temporal pattern with similarities to both GABA and osmolyte transporters. Further investigation of BGT1 regulation in the brain is warranted. PMID:21219332

Rowley, Nicole M.; Smith, Misty; Lamb, John G.; Schousboe, Arne; White, H. Steve