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PubMed1993

Significance of chloride channel activation in the gamma-aminobutyric acid induced growth hormone secretion in the neonatal rat pituitary.

Growth hormone (GH) secretion of the neonatal pituitary is stimulated by tau-aminobutyric acid (GABA) (1,2). Since in most cases GABA is known to act by increasing postsynaptic membrane permeability to chloride ions we tested the importance of chloride channel activation in the GH stimulatory effect of GABA in the neonatal pituitary. In the absence of chloride in the superfusion medium GABA was without effect on GH secretion of the neonatal pituitaries and its effect was attenuated by chloride channel inhibitors. The effect of growth hormone releasing hormone (GHRH) on GH secretion was attenuated in the chloride-free media, but it was not affected by simultaneous administration of chloride channel blockers. The present study indicates that GH stimulatory effect of GABA in the neonatal pituitaries might involve chloride channel activation probably resulting in secondary activation of calcium channels.

Animals↗
PubMed2003

The Vogel conflict test: procedural aspects, gamma-aminobutyric acid, glutamate and monoamines.

A multitude of mechanisms are involved in the control of emotion and in the response to stress. These incorporate mediators/targets as diverse as gamma-aminobutyric acid (GABA), excitatory amino acids, monoamines, hormones, neurotrophins and various neuropeptides. Behavioural models are indispensable for characterization of the neuronal substrates underlying their implication in the etiology of anxiety, and of their potential therapeutic pertinence to its management. Of considerable significance in this regard are conflict paradigms in which the influence of drugs upon conditioned (trained) behaviours is examined. For example, the Vogel conflict test, which was introduced some 30 years ago, measures the ability of drugs to release the drinking behaviour of water-deprived rats exposed to a mild aversive stimulus ("punishment"). This model, of which numerous procedural variants are discussed herein, has been widely used in the evaluation of potential anxiolytic agents. In particular, it has been exploited in the characterization of drugs interacting with GABAergic, glutamatergic and monoaminergic networks, the actions of which in the Vogel conflict test are summarized in this article. More recently, the effects of drugs acting at neuropeptide receptors have been examined with this model. It is concluded that the Vogel conflict test is of considerable utility for rapid exploration of the actions of anxiolytic (and anxiogenic) drugs. Indeed, in view of its clinical relevance, broader exploitation of the Vogel conflict test in the identification of novel classes of anxiolytic agents, and in the determination of their mechanisms of action, would prove instructive.

Animals↗
PubMed1990

Effects of gamma-aminobutyric acid on skate retinal horizontal cells: evidence for an electrogenic uptake mechanism.

In the retinae of many vertebrates, there are classes of horizontal cell that probably utilize gamma-aminobutyric acid (GABA) as a neurotransmitter. As with other amino acid transmitter agents, the postsynaptic action of GABA is thought to be terminated by uptake into neurons and glia surrounding the release site. The present study examined whether an uptake system for GABA could be detected in isolated skate horizontal cells by means of electrophysiological methods. Pressure ejection of GABA onto voltage-clamped horizontal cells produced an inward current that showed no sign of desensitization regardless of the GABA concentration. The dose-response relationship followed simple Michaelis-Menten kinetics, with a half-maximal response elicited at approximately 110 microM. Nipecotic acid produced a similar current and reduced the responses to GABA when introduced in the bath solution prior to the GABA pulse. On the other hand, application of 500 microM muscimol or 1 mM baclofen, GABAA and GABAB receptor agonists, respectively, were completely without effect. The GABA-induced current was not blocked by superfusion with 500 microM bicuculline, 500 microM picrotoxin, or 500 microM phaclofen. However, the responses to GABA were abolished when the cells were superfused in Ringer's solution in which choline or lithium had been substituted for sodium, and were reduced when the extracellular chloride concentration was decreased from 266 mM to 16 mM. Current-voltage data showed a maximal response to GABA when the cells were held at or below their resting potential. At more depolarized levels, the inward current became progressively smaller until, near +50 mV, it could no longer be detected; over the range tested (-90 to +50 mV), the response never reversed into an outward current. These findings suggest that the GABA-induced currents in skate horizontal cells are mediated by an electrogenic uptake mechanism.

Animals↗
PubMed1987

Delayed transneuronal death of substantia nigra neurons prevented by gamma-aminobutyric acid agonist.

In an investigation of the mechanism by which brain lesions result in delayed degeneration of neurons remote from the site of injury, neurons within the caudate nucleus of rats were destroyed by local injection of the excitotoxin ibotenic acid. Treatment resulted in the rapid degeneration of the striatonigral pathway including projections containing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and delayed transneuronal death of neurons in the substantia nigra pars reticulata. The distribution of nigral cell loss corresponded to the loss of GABAergic terminals. Neuronal death was prevented by long-term intraventricular infusion of the GABA agonist muscimol. Delayed transneuronal degeneration may be produced by neuronal disinhibition consequent to loss of inhibitory inputs. Replacement of inhibitory transmitters by suitable drugs may prevent some forms of delayed neuronal death.

Animals↗
PubMed1994

The astrocyte response to gamma-aminobutyric acid attenuates with age in the rat optic nerve.

There is increasing evidence that glial cells respond to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and astrocytes have been shown to possess GABAA receptors both in vivo and in vitro. A recent study by Sakatani et al. (Proc. R. Soc. Lond. B247, 155 (1992)) demonstrated the transient expression of functional GABAA receptors in the developing rat optic nerve, but axonal and glial components of the response were not distinguished. To help address this problem, we have determined the electrophysiological response to GABA in astrocytes of the isolated intact optic nerves from neonatal rats, identified morphologically following intracellular injection of horseradish peroxidase. Astrocytes responded to GABA by a GABAA receptor-mediated depolarization which attenuated gradually during post-natal development; astrocytes in 21-day-old nerves were not observed to respond to GABA. The results indicate the transient presence of functional GABAA receptors in developing rat optic nerve astrocytes in situ, and we speculate upon a role for GABA in glial signalling and the organization of axonglial interrelations during development.

Aging↗
PubMed1999

Colocalization of gamma-aminobutyric acid immunoreactivity and acetylcholinesterase activity in nerve fibers of the mouse adrenal gland.

The present immunohistochemical and enzyme histochemical study showed gamma-aminobutyric acid (GABA) immunoreactivity and acetylcholinesterase (AChE) activity in the mouse adrenal gland. Weak GABA immunoreactivity was seen in clusters of chromaffin cells showing noradrenaline fluorescence. This finding suggests that both GABA and noradrenaline may be released from the granules of noradrenaline cells by adequate stimuli. GABA-immunoreactive varicose nerve fibers densely contacted adrenaline cells and large ganglion cells, but they were sparse in the periphery of clusters of noradrenaline cells. AChE activity was strong in a few large ganglion cells and weak in chromaffin cells showing noradrenaline fluorescence, and was found in numerous nerve bundles and fibers of the medulla. AChE-active nerve fibers more densely contacted noradrenaline cells than adrenaline cells. By using double labeling technique, numerous GABA-immunoreactive nerve fibers in the medulla were reactive for AChE in the same sections. These results suggest that both GABA and acetylcholine may be colocalized in the intra-adrenal nerve fibers and may have some secretory effects on the chromaffin cells.

Acetylcholinesterase↗
PubMed1990

Inverse modulation of gamma-aminobutyric acid- and glycine-induced currents by progesterone.

The ability of certain synthetic and endogenous steroids to modulate neuronal responses to gamma-aminobutyric acid (GABA) is well documented, but little is known of the effect of steroids on glycine responses. We show here that in voltage-clamped neurons progesterone (10-100 microM) itself enhances GABA-induced chloride currents but, surprisingly, antagonizes those induced by glycine. Some, but not all, progesterone metabolites also display these effects. The effects of progesterone on GABA and glycine responses are dose dependent, with EC50 values of 26 and 16 microM and maxima of +156 and -60%, respectively. Progesterone and its reduced metabolite 5 alpha-pregnan-3 alpha-ol-20-one potentiate GABA responses by acting through a common site. The site through which progesterone acts to inhibit glycine responses is distinct from the strychnine and glycine binding sites. These results not only provide an important distinction between chloride-mediated GABA and glycine responses but also suggest that endogenous progesterone or its metabolites may differentially modulate the inhibitory actions of these two neurotransmitters.

Animals↗
PubMed1989

Release of endogenous taurine and gamma-aminobutyric acid from brain slices from the adult and developing mouse.

The spontaneous and potassium-stimulated release of endogenous taurine and gamma-aminobutyric acid (GABA) from cerebral cortex and cerebellum slices from adult and developing mice was studied in a superfusion system. The spontaneous release of GABA was of the same magnitude in slices from adult and developing mice, but the spontaneous release of taurine was considerably greater in the adults. The potassium-stimulated release of GABA from cerebral cortex slices was about five times greater in adult than in 3-day-old mice, but the potassium-stimulated release of taurine was more than six times greater in 3-day-old than in adult mice. In cerebellar slices from 7-day-old mice, potassium stimulation also evoked a massive release of taurine, whereas the evoked release from slices from adult mice was rather negligible. Also in cerebellar slices the potassium-stimulated release of GABA exhibited the opposite quantitative pattern. The stimulated release of both GABA and taurine was partially calcium dependent. The results suggest that taurine may be an important regulator of excitability in the developing brain.

Aging↗
PubMed1982

Two actions of gamma-aminobutyric acid on the responses of the isolated basilar artery from the rabbit.

1 In the isolated basilar artery of the rabbit, gamma-aminobutyrate acid (GABA) (ED50 +/- s.e. mean, 2.4 +/- 1.1 x 10(-5) M) produced a relaxation, if the tone had been increased with 5-hydroxytryptamine (5-HT). 2 3-Aminoproprane sulphonic acid (3-APS) produced a similar, but smaller relaxation, while baclofen had no effect. The relaxation produced by GABA was inhibited by bicuculline. 3 Transmural electrical stimulation produced a reproducible contraction of the isolated basilar artery. In 9 out 14 preparations GABA (ED50 +/- s.e. mean, 5.6 +/- 2.1 x 10(-7) M) caused a reduction of the response, with a maximum of 49.2 +/- 4.3%. Bicuculline did not inhibit these responses to GABA. 4 Baclofen (ED50 +/- s.e. mean, 6.8 +/- 1.4 x 10(-7) M) produced a similar inhibition (47.4 +/- 3.2% maximum) but 3-APS had no effect. 5 GABA (10(-4) M) had no effect on the tone of isolated mesenteric or internal carotid arteries from the rabbit, whether or not the tone was increased with 5-HT. Similarly, GABA (10(-4) M) did not produce any change in the responses to transmural stimulation in isolated mesenteric or internal carotid arteries. 6 These findings are consistent with the presence of two types of GABA receptor on the rabbit basilar artery.

Animals↗
PubMed2004

[Effects of exogenous gamma-aminobutyric acid on antioxidant enzyme activity and reactive oxygen content in muskmelon seedlings under nutrient solution hypoxia stress].

The effects of exogenous gamma-aminobutyric acid (GABA) on antioxidant defense system and reactive oxygen species (ROS) in seedlings of two varieties with different resistance to hypoxia stress were studied under hypoxia stress in a nutrient solution culture system. The results showed that GABA treatments enhanced the activities of antioxidant enzyme including SOD (Fig. 1), POD (Fig. 2), CAT (Fig. 3), while the concentrations of H2O2 (Fig. 4), O(-.)2 (Fig. 5), MDA (Fig. 6) decreased under hypoxia stress. Among the treatments of three different GABA concentrations, the effect of 50 mmol/L GABA treatment was better than that of 25 mmol/L GABA and 100 mmol/L GABA treatments. The effect of treatment with GABA in "Dongfang xingguang" seedlings, which had stronger hypoxia-resistance to hypoxia stress, were better than that in "Xiyu No.1" seedlings which had lower hypoxia-resistance. It indicates that GABA treatment of exogenous spraying to leaves can increase the activities of antioxidant enzyme under the hypoxia stress and plays an important role in enhancing the resistance to hypoxia stress of muskmelon seedlings through keeping low ROS contents.

Antioxidants↗
PubMed1998

Hypergravity exposure decreases gamma-aminobutyric acid immunoreactivity in axon terminals contacting pyramidal cells in the rat somatosensory cortex: a quantitative immunocytochemical image analysis.

Quantitative evaluation of gamma-aminobutyric acid immunoreactivity (GABA-IR) in the hindlimb representation of the rat somatosensory cortex after 14 days of exposure to hypergravity (hyper-G) was conducted by using computer-assisted image processing. The area of GABA-IR axosomatic terminals apposed to pyramidal cells of cortical layer V was reduced in rats exposed to hyper-G compared with control rats, which were exposed either to rotation alone or to vivarium conditions. Based on previous immunocytochemical and behavioral studies, we suggest that this reduction is due to changes in sensory feedback information from muscle receptors. Consequently, priorities for muscle recruitment are altered at the cortical level, and a new pattern of muscle activity is thus generated. It is proposed that the reduction observed in GABA-IR of the terminal area around pyramidal neurons is the immunocytochemical expression of changes in the activity of GABAergic cells that participate in reprogramming motor outputs to achieve effective movement control in response to alterations in the afferent information.

Animals↗
PubMed1999

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

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

Adult↗
PubMed1991

gamma-Aminobutyric acid (GABA) induces a receptor-mediated reduction in GABAA receptor alpha subunit messenger RNAs in embryonic chick neurons in culture.

gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in brain, is known to interact with a subclass of receptors that activate a ligand-gated chloride ion channel. Exposure of cultured embryonic chick neurons to physiological concentrations of GABA results in a time-dependent down-regulation of these GABAA receptors. To delineate the cellular mechanism(s) responsible for agonist-induced down-regulation of GABAA receptors we quantified the levels of GABAA receptor alpha subunit messenger RNAs, which encode the subunit(s) containing agonist recognition site(s), and observed a marked reduction in alpha subunit mRNAs following exposure of embryonic chick neurons to GABA. Both the down-regulation of GABAA receptors and the reduction in alpha subunit mRNAs induced by GABA were completely antagonized by the specific GABAA receptor antagonist SR-95531. These data demonstrate the presence of an agonist-induced receptor-mediated mechanism for regulating the expression of receptor subunit-encoding mRNAs that may be involved in the development of tolerance to the pharmacological actions of drugs known to act via GABAA receptors.

Animals↗
PubMed1989

Synaptosomal uptake of choline and of gamma-aminobutyric acid: effects of ethanol and of dimethylsulfoxide.

We have characterized the interactive effects of ethanol and dimethylsulfoxide on synaptosomal uptakes of gamma-aminobutyric acid (GABA) and choline. Ethanol is a membrane-disordering agent which has been shown to inhibit synaptosomal high-affinity choline uptake at pharmacologically relevant ethanol concentrations, and to inhibit synaptosomal GABA uptake at higher ethanol concentrations. Dimethylsulfoxide (DMSO) is an organic solvent which has been shown to have a stabilizing effect on artificial phospholipid bilayers, and to have effects on conformation of and cation binding to brain (Na+, K+)-ATPase which are opposite those of ethanol. DMSO alone (2-10% v/v) inhibited synaptosomal uptakes of GABA and of choline in a concentration-dependent fashion, with choline uptake inhibited to a greater degree than GABA uptake. This result is qualitatively similar to the effects of ethanol on these uptake processes. DMSO at low concentrations (0.3-1.5% v/v) had no effect on inhibition of GABA and choline uptake by 0.6 M ethanol, and higher DMSO concentrations resulted only in further inhibition. Similarly, ethanol (0.3 M) had no effect on inhibition of GABA and choline uptake by 5% (v/v) DMSO, and higher ethanol concentrations (0.6-1.2 M) resulted only in further inhibition. We conclude that the inhibiting effects of ethanol on synaptosomal GABA and choline uptake are not reversed by DMSO.

Animals↗
PubMed2005

Activation of gamma-aminobutyric acid GAT-1 transporters on glutamatergic terminals of mouse spinal cord mediates glutamate release through anion channels and by transporter reversal.

The effects of gamma-aminobutyric acid (GABA) on the release of glutamate from mouse spinal cord nerve endings have been studied using superfused synaptosomes. GABA elicited a concentration-dependent release of [3H]D-aspartate ([3H]D-ASP; EC50= 3.76 microM). Neither muscimol nor (-)baclofen mimicked GABA, excluding receptor involvement. The GABA-evoked release was strictly Na+ dependent and was prevented by the GABA transporter inhibitor SKF89976A, suggesting involvement of GAT-1 transporters located on glutamatergic nerve terminals. GABA also potentiated the spontaneous release of endogenous glutamate; an effect sensitive to SKF89976A and low-Na+-containing medium. Confocal microscopy shows that the GABA transporter GAT-1 is coexpressed with the vesicular glutamate transporter vGLUT-1 and with the plasma membrane glutamate transporter EAAT2 in a substantial portion of synaptosomal particles. The GABA effect was external Ca2+ independent and was not decreased when cytosolic Ca2+ ions were chelated by BAPTA. The glutamate transporter blocker DL-TBOA or dihydrokainate inhibited in part (approximately 35%) the GABA (10 microM)-evoked [3H]D-ASP release; this release was strongly reduced by the anion channel blockers niflumic acid and NPPB. GABA, up to 30 microM, was unable to augment significantly the basal release of [3H]glycine from spinal cord synaptosomes, indicating selectivity for glutamatergic transmission. It is concluded that GABA GAT-1 transporters and glutamate transporters coexist on the same spinal cord glutamatergic terminals. Activation of these GABA transporters elicits release of glutamate partially by reversal of glutamate transporters present on glutamatergic terminals and largely through anion channels.

Animals↗
PubMed2004

Characteristic expression of gamma-aminobutyric acid and glutamate decarboxylase in rat jejunum and its relation to differentiation of epithelial cells.

AIM: To investigate the expression between gamma-aminobutyric acid (GABA) and glutamate decarboxylase and its relation with differentiation and maturation of jejunal epithelial cells in rat jejunum. METHODS: Immunohistochemical expression of GABA and glutamate decarboxylase (GAD, including two isoforms, GAD65 and GAD67) was investigated in rat jejunum. Meanwhile, double staining was performed with GAD65 immunohistochemistry, followed by lectin histochemistry of fluorescent wheat germ agglutinin. Furthermore, evaluation of cell kinetics in jejunum was conducted by (3)H-thymidine autoradiography and immunohistochemistry using a monoclonal antibody to proliferating cell nuclear antigen (PCNA). RESULTS: The cells showing positive immunoreactivity GABA and GAD65 were mainly distributed in the villi in rat jejunum, while jejunal epithelial cells were negative for GAD67. Positive GABA or GAD65 staining was mainly located in the cytoplasm and along the brush border of epithelial cells in the middle and upper portions. In addition, a few GABA and GAD65 strongly positive cells were scattered in the upper two thirds of jejunal villi. Double staining showed that GAD65 immunoreactivity was not found in goblet cells. (3)H-thymidine-labeled nuclei were found in the lower and middle portions of jejunal crypts, which was consistent with PCNA staining. Therefore, GABA and GAD65 were expressed in a maturation or functional zone. CONCLUSION: The characteristic expression of GABA and GAD suggests that GABA might be involved in regulation of differentiation and maturation of epithelial cells in rat jejunum.

Animals↗
PubMed1981

Possible involvement of gamma-aminobutyric acid in growth hormone release induced by a Met5-enkephalin analog in conscious rats.

The interaction between opioid peptides and gamma-aminobutyric acid (GABA) in regulating GH secretion was studied in unanesthetized male rats with chronically implanted intraatrial catheters. GH secretion was pulsatile with GH bursts (mean +/- SE, 259.1 +/- 70.3 ng/ml) occurring at regular intervals (mean +/- SE, 3.6 +/- 0.2 h) in control rats. When a potent met5-enkephalin analog, FK 33-824 ([D-Ala,MePhe4,Met(O)-ol]enkephalin; 10 micrograms/100 g BW), was injected iv in the interval between two anticipated spontaneous GH bursts, plasma GH abruptly increased to a peak value of 716.0 +/- 144.9 ng/ml 20 min after the injection, and the following spontaneous GH burst appeared at longer intervals than expected (5.0 +/- 0.4 h, P less than 0.025 vs. control). The plasma GH increase induced by FK 33-824 was blunted by a specific opiate antagonist, naloxone (125 micrograms/100 g BW, iv), and the following spontaneous GH bursts occurred at the same time as in controls. The plasma GH response to FK 33-824 was significantly inhibited by two GABA antagonists, picrotoxin (0.3 mg/100 g BW, iv) and bicuculline (60 micrograms/100 g BW, iv), with peak GH values of 24.6 +/- 6.4 and 136.4 +/- 35.2 ng/ml, respectively (P less than 0.01 vs. FK 33-824 alone). The following natural GH bursts were also inhibited by these GABA antagonists (50.1 +/- 21.3 and 35.3 +/- 9.6 ng/ml; P less than 0.01 vs. control). These findings suggest the possible involvement of GABA in GH release induced by opioid peptides in the rat.

Animals↗
PubMed1996

Accumulation of gamma-aminobutyric acid in diabetic rat retinal Müller cells evidenced by electron microscopic immunocytochemistry.

PURPOSE: To evaluate possible changes in the distribution of gamma-aminobutyric acid (GABA) in diabetic rat retinas. METHODS: GABA distributions in the normal control and diabetic rat retinas were determined by a quantitative immunogold electron microscopic immunocytochemistry with anti-GABA antibody. GABA immunoreactivities (GABA-IR) in the retinas were visualized as bound gold colloidal particles in electron microscopy, and the average densities were calculated in each layer or in each kind of cells. The amounts of GABA-IR were statistically compared between normal control and diabetic rat retinas. RESULTS: In the normal control rat retinas, the amounts of GABA-IR was most abundant in the inner portion of the inner nuclear layer, followed by the inner plexiform layer. GABA-IR in amacrine cells ranged from the background level to the highest throughout the retina. Although the distribution pattern of GABA-IR in the diabetic rat retinas was similar to that of the normal control, GABA-IR increased significantly in the inner segment, the outer nuclear layer, and the outer plexiform layer (P < 0.05, by the analysis of variance), and in Müller cells (P < 0.001, by Mann-Whitney's U-test) of the diabetic rat retinas. However, pathologic accumulation of GABA-IR was not demonstrated in amacrine cells of the diabetic rat retinas. CONCLUSIONS: These results supported the accumulation of GABA in diabetic rat retinal Müller cells evidenced by light microscopic immunocytochemistry previously. It was suggested that GABA accumulation represents one of the functional deterioration of Müller cells in diabetic rat retinas.

Animals↗