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PubMed1995

Mechanism of action of gamma-aminobutyric acid on frog melanotrophs.

We have previously demonstrated that gamma-aminobutyric acid (GABA) is a potent regulator of secretory and electrical activity in melanotrophs of the frog pituitary. The aim of the present study was to investigate the intracellular events which mediate the response of melanotrophs to GABA. We first observed that GABA (1-100 microM) inhibited both basal and forskolin-stimulated cyclic AMP (cAMP) formation. The inhibitory effect of GABA on cAMP levels was mimicked by the GABAB receptor agonist baclofen (100 microM) and totally abolished by a 4-h pretreatment with pertussis toxin (0.1 microgram/ml). In contrast, the specific GABAA agonist 3-aminopropane sulphonic acid (3APS) did not affect cAMP production. Both GABA and 3APS (100 microM each) induced a biphasic effect on alpha-MSH release from perifused frog neurointermediate lobes, i.e. a transient stimulation followed by an inhibition of alpha-MSH secretion. Administration of forskolin (10 microM) prolonged the stimulatory phase and attenuated the inhibitory phase evoked by GABA and 3APS, indicating that cAMP modulates the response of melanotrophs to GABAA agonists. Ejection of 3APS (1 microM) in the vicinity of cultured melanotrophs caused a massive increase in intracellular calcium concentration ([Ca2+]i). The stimulatory effect of 3APS on [Ca2+]i was abolished when the cells were incubated in a chloride-free medium. The formation of inositol trisphosphate was not affected by 3APS, suggesting that the increase in [Ca2+]i cannot be ascribed to mobilization of intracellular calcium stores. omega-Conotoxin did not alter the secretory response of frog neurointermediate lobes to 3APS, while nifedipine blocked the stimulation of alpha-MSH secretion induced by 3APS. In conclusion, the present data indicate that, in frog pituitary melanotrophs, (i) the stimulatory phase evoked by GABAA agonists can be accounted for by an influx of calcium through L-type calcium channels, (ii) the inhibitory effect evoked by GABAB agonists can be ascribed to inhibition of adenylate cyclase activity and (iii) cAMP attenuates the inhibitory phase evoked by GABAA agonists. Taken together, these data suggest that activation of GABAB receptors may modulate GABAA receptor function.

Adenylyl Cyclases↗
PubMed1983

Membrane potential changes induced by gamma-aminobutyric acid and related amino acids in the rabbit superior cervical ganglion.

The effects of gamma-aminobutyric acid (GABA), delta-aminolaevulinic acid (DALA) and delta-aminovaleric acid(DAVA) on membrane potential were studied in the isolated rabbit superior cervical ganglion (SCG) using external electrodes(sucrose-gap apparatus). GABA(5.2-1031 micrograms), DALA(335-1676 micrograms), and DAVA(206.2-1563 micrograms) produced a dose-dependent depolarization in the rabbit SCG. The mean (+/- SEM) ED 50s for the depolarizations produced by GABA, DALA, and DAVA were 58.8 +/- 2.2 micrograms, 733 +/- 16.1 micrograms, and 845 +/- 12.9 micrograms, n = 6, respectively. The mean (+/- SEM) maximum depolarizations were: 1.4 +/- 0.12 mV, 0.91 +/- 0.1 mV, and 0.95 +/- 0.1 mV, n = 6, respectively. It is concluded that GABA and the related aminoacids produce depolarizations in the rabbit SCG, which are similar in shape and duration but larger in amplitude than those produced in the rat SCG.

Amino Acids↗
PubMed1988

gamma-Aminobutyric acid release from synaptosomes prepared from rats treated with isonicotinic acid hydrazide and gabaculine.

The potassium-stimulated release of gamma-aminobutyric acid (GABA) from synaptosomes was determined in preparations from control rats and from rats treated with a convulsant agent [isonicotinic acid hydrazide (INH)] and an anticonvulsant agent (gabaculine). INH treatment brought about a significant decrease in Ca2+-dependent release of GABA with no effect on Ca2+-independent release, whereas gabaculine caused an increase in Ca2+-independent release with no effect on Ca2+-dependent release of GABA. Thus, the anticonvulsant action of gabaculine was not a simple reversal of the effects of INH on GABA release. The results indicate that there are at least two pools of GABA in nerve endings and support the hypothesis that exogenous GABA is taken up first into a pool that supplies GABA for Ca2+-independent release and then is transferred to a second pool (Ca2+-dependent releasable), where it mixes with newly synthesized GABA.

Animals↗
PubMed1997

Immunocytochemical localization of gamma-aminobutyric acid plasma membrane transporters in the tiger salamander retina.

Gamma-aminobutyric acid (GABA) plasma membrane transporters (GATs) play an important role in regulating GABA neurotransmission in the nervous system. The distribution of two GATs, GAT 1 and GAT 3, in salamander retina was investigated by using affinity-purified polyclonal antisera directed to the predicted C-terminals of rat GAT 1 and rat GAT 3. GAT 1-immunoreactivity (-IR) was found in type IB and IIB orthotopic bipolar cells (BCs) located in the distal and middle of the inner nuclear layer (INL), respectively; in type IIA and IA amacrine cells (ACs) located in the middle and proximal INL, respectively; and in interplexiform cells and cells in the ganglion cell layer (GCL). No detectable staining was found in horizontal cells (HCs) or in structures resembling Müller cells. GAT 1-immunoreactive fibers were present in the outer plexiform layer (OPL) and inner plexiform layer (IPL) in three bands corresponding to the three bands previously reported to be GABA-IR. GAT 3 antibodies labeled fewer cells and cell types than GAT 1 antibodies. GAT 3-IR was localized to type IIA and IA ACs and cells in the GCL, but not to BCs, HCs, or Müller cell-like structures. There was weak labeling of the OPL and stronger labeling of the IPL, with three distinct bands at the same depth as observed with GAT 1-IR. Double-labeling showed that the majority of GAT 1-IR BCs (88%), ACs (88%), and cells in the GCL (78%) colocalized with GABA-IR. The present study provides the first direct evidence of the expression of two GAT subtypes in neurons of nonmammalian retinas. These transporters could regulate GABA neurotransmission by reuptake and termination of GABA's action and, perhaps, by GABA release mechanisms. The presence of GAT 1-IR/GABA-IR bipolar cells further supports our earlier observations that a subgroup of orthotopic bipolar cells are likely to be GABAergic.

Ambystoma↗
PubMed2001

Overexpression of gamma-aminobutyric acid transporter subtype I leads to cognitive deterioration in transgenic mice.

AIM: To explore the physiological role of gamma-aminobutyric acid transporter subtype I (GAT1) in cognition. METHODS: Transgenic mice were produced by pronuclei microinjection method. Integration of transgene was identified by Southern-blot and PCR analysis in various generations. Level of GAT1 mRNA in a variety of tissues was evaluated by semi-quantitative RT-PCR analysis. GAT1 protein was detected by immunofluorescence and histochemistry analysis. Associative learning capacity was analyzed by conditioned avoidance task. Memory retention was assessed by novel object recognition test. Morphology of synaptosomes was examined by electron microscope. RESULTS: Four independent founder mice bearing various copies of transgene were generated. GAT1 was evidently overexpressed at both mRNA and protein level in a variety of tissues from transgenic mice. In comparison with wild-type mice, transgenic mice exhibited significantly declined associative learning capacity (P < 0.01) and decreased memory retention (P < 0.01 in 1-h-retention, and P < 0.05 in 1-d-retention). In addition, the amount of asymmetric synapses in the brain of transgenic mice was reduced approximately by 24 %, relative to wild-type mice. CONCLUSION: Overexpression of GAT1 in mice results in cognitive deterioration, indicating that the alteration in the expression of gamma-aminobutyric acid transporters is involved in the pathophysiological mechanism underlying some cognitive deficiencies.

Animals↗
PubMed1985

Synthesis and activity of 5-(aminomethylene)-1,3-cyclohexanediones: enolic analogues of gamma-aminobutyric acid.

Eight 1,3-cyclohexanediones with an aminoalkyl side chain in the 5-position were synthesized as rigid enolic analogues of GABA (gamma-aminobutyric acid). Biochemical investigations about their abilities to displace [3H]GABA and [3H]baclofen [beta-(p-chlorophenyl)-gamma-aminobutyric acid] in binding studies or to inhibit the high-affinity sodium-dependent GABA uptake showed that these compounds were generally devoid of affinity for the two GABA receptors and for the GABA carrier. Only compound 1 exhibited a weak affinity in the GABA-A binding experiments (IC50 = 6.5 X 10(-5) M). Graphic computer modeling was applied in an attempt to explain this activity in comparison to some reference GABA agonists. Electrophysiological studies on dorsal root ganglia (DRG) also excluded agonistic or antagonistic properties on GABA-A or GABA-B receptor models but pointed out an atypical prolongation of Ca2+-dependent action potential for compound 1.

Action Potentials↗
PubMed1980

Bidirectional movement of gamma-aminobutyric acid in rat spinal cord slices.

The bidirectional movement of GABA (gamma-aminobutyric acid) was studied in slices of rat spinal cord which were incubated in small volumes of medium. The appearance in the medium of endogenous GABA and the disappearance from the medium of [14C]GABA were used to calculate the rates of unidirectional uptake and unidirectional release of GABA. Under these conditions, no net uptake of GABA was observed when slices were incubated in media containing concentrations of gABA as high as 25 microM. Elevated potassium (60 mM) stimulated the unidirectional release of endogenous GABA from spinal cord slices by a calcium-dependent process. Ouabain (0.1 mM) more than doubled the unidirectional release of endogenous GABA in a calcium-independent manner, while unidirectional uptake was inhibited by 44%. Nipecotic acid (1.0 mM) stimulated unidirectional release and inhibited unidirectional uptake of GABA.

Animals↗
PubMed2005

Protective effects of gamma-aminobutyric acid in rats with streptozotocin-induced diabetes.

The effects of gamma-aminobutyric acid (GABA) in rats with experimental diabetes mellitus were examined. Diabetes mellitus was induced in adult male Wistar rats by streptozotocin (STZ) injection. Oral administration of GABA (100 or 200 mg/kg body weight/d) for 10 d to the diabetic rats resulted in a significant decrease in their serum glucose level. GABA also reduced the level of glycosylated protein in serum, indicating an improvement of hyperglycemic conditions. Rats with STZ-induced diabetes showed arrested body weight gain and an increase in both liver and kidney weight, whereas oral administration of GABA attenuated the organ hypertrophy induced by hyperglycemia. In addition, the degree of serum thiobarbituric acid (TBA)-reactive substance level was significantly lower in the rats treated with 100 mg GABA, and the degree of TBA-reactive substance in the liver and kidney was reduced by GABA in a dose-dependent manner. These results suggest that GABA treatment protects against the development of diabetic complications resulting from impaired glucose metabolism and enhanced oxidative stress.

Animals↗
PubMed2002

The role of glutamate and gamma-aminobutyric acid in fear extinction: clinical implications for exposure therapy.

Although much is now known about the neural basis of fear acquisition, the mechanisms of fear inhibition or suppression remain largely obscure. Fear inhibition is studied in the laboratory through the use of an extinction procedure, in which an animal (typically a rat) is exposed to nonreinforced presentations of a conditioned stimulus (CS; e.g., a light or tone) that had previously been paired with a fear-inducing unconditioned stimulus (US; e.g., a mild footshock). Over the course of such training, the conditioned fear response exhibited by the rat in the presence of the CS is reduced in amplitude and frequency. This procedure is analogous to those employed in the treatment of fear dysregulation in humans, which typically involve exposure to the feared object in the absence of any overt danger. Recent work on the neural basis of extinction indicates that the neurotransmitters gamma-aminobutyric acid (GABA) and glutamate are critically involved. Gamma-aminobutyric acid may act to inhibit brain areas involved in fear learning (e.g., the amygdala), and glutamate, acting at N-methyl-D-aspartate receptors, may play a role in the neural plasticity that permits this GABA-mediated inhibition to be exerted appropriately. These insights have significant implications for the conduct of extinction-based clinical interventions for fear disorders.

Amygdala↗
PubMed1984

Sheep pineal beta-adrenoceptor function--interaction with gamma-aminobutyric acid.

To clarify the role and site of action of gamma-aminobutyric acid (GABA) in ovine pineal glands, we have investigated the effects of aminooxyacetic acid (AOAA), an inhibitor of GABA transaminase, on endogenous GABA content and beta-adrenoceptor mediated pineal function in Merino sheep. A significant elevation of endogenous GABA levels was noted in the glands, but no effect was observed on radioligand binding in vitro to pineal beta-adrenoceptors following in vivo administration of AOAA. Incubation of washed pineal membranes with GABA or AOAA had no effect on ligand binding to beta-adrenoceptors. Incubation of Merino pineal slices with GABA inhibited isoprenaline-stimulated but not basal serotonin N-acetyltransferase (NAT) activity. Incubation of whole pineal homogenates with GABA was without effect on either isoprenaline-stimulated or basal adenyl cyclase activity. Thus, Merino pineal glands resemble bovine pineals in that beta-adrenoceptor mediated melatonin biosynthesis in both species may be regulated in part by GABA. Our results indicate that GABA may exert its effect on Merino pineal NAT activity at a locus distal to the site of action of adenyl cyclase; however, the detailed mechanism and physiological role of this regulation remain to be elucidated.

Acetyltransferases↗
PubMed1985

Pantoyl-gamma-aminobutyric acid facilitates cholinergic function in the central nervous system.

Pantoyl-gamma-aminobutyric acid (P-GABA) administered i.p. inhibited scopolamine- and atropine-induced locomotor activities in mice, but did not inhibit methamphetamine- and apomorphine-induced locomotor activities. In radiolabeled ligand binding experiments, P-GABA did not inhibit the bindings of [3H]quinuclidinyl benzilate, [3H]spiroperidol and [3H]apomorphine to rat brain membranes, but inhibited that of [3H]muscimol. GABA and P-GABA enhanced K+ (25 mM)-induced release of [3H]acetylcholine from slices of the cerebral cortex and hippocampus dose-dependently, and their effects were antagonized by bicuculline but not by tetrodotoxin. These results suggest that P-GABA binds to GABA receptors causing enhanced cholinergic neurotransmission in the central nervous system. The results are discussed in relation to the clinical use of P-GABA in treatment of Alzheimer's disease and senile dementia of the Alzheimer type.

Acetylcholine↗
PubMed1983

High anticonvulsant potency of gamma-aminobutyric acid (GABA)mimetic drugs in gerbils with genetically determined epilepsy.

Seven GABAmimetic drugs, namely cetyl gamma-aminobutyric acid (cetyl GABA), 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol, progabide, aminooxyacetic acid, alpha-acetylenic GABA, (-)-nipecotic acid ethyl ester and (+/-)-cis-4-hydroxynipecotic acid methyl ester, were tested for their potency to block "major" (generalized clonic-tonic) seizures in gerbils, induced by blowing at the animals with compressed air. Valproic acid was included as a reference standard. All drugs proved able to protect gerbils from induced seizures. Most effective were 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol (ED50, 1.3 mg/kg i.p.), aminooxyacetic acid (0.9), cetyl GABA (4.5) and gamma-acetylenic GABA (2.1). A comparison with anticonvulsant ED50 values of common antiepileptics in the gerbil showed that these four GABAmimetics were clearly more potent than phenobarbital, phenytoin, carbamazepine, ethosuximide and valproic acid and were only surpassed in potency by diazepam. Furthermore, most GABAmimetics proved strikingly more active in the gerbil compared with the classical electroshock and pentylenetetrazol seizure models in mice. After administration of gamma-acetylenic GABA, GABA increases in the brain of only about 40% were found sufficient to reach almost complete seizure protection in gerbils. The present data are compatible with the possibility that the GABA system is critically involved in the seizure-prone state in the gerbil.

Alkynes↗
PubMed2001

N-Phthaloyl gamma-aminobutyric acid affects biochemical circadian rhythms in Wistar rats.

N-Phthaloyl gamma-aminobutyric acid (P-GABA) was administered to Wistar rats and 24 hr rhythms of glucose, cholesterol, total protein and lactic acid levels in blood were studied under semi-natural light dark conditions. P-GABA administration caused desynchronisation of the rhythms; while glucose and lactic acid rhythms were advanced, cholesterol and total protein rhythms were delayed. Since GABA is being involved in conveying dark information to the clock, exogenous administration of P-GABA may reduce the photic information received by the clock. The results could be explained by slightly less than 1 hr daily delays (or) advances respectively which would bring the peak times to the points 21 days after the start of administration.

Animals↗
PubMed1986

gamma-Aminobutyric acid agonists and antagonists alter chloride flux across brain membranes.

gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, increases membrane chloride conductance. Previously, we reported that GABA increases 36Cl- uptake by membrane vesicles (microsacs) prepared from mouse brain. Employing this technique, we found that the GABAA agonists, muscimol, isoguvacine, 4,5,6,7-tetrahydroisoxazolo(5,4-C)pyridine-3-ol, and 3-amino-1-propane sulfonate, all produced a concentration-dependent increase in 36Cl- influx, but baclofen, a GABAB agonist, failed to alter 36Cl- flux. Inhibition of GABA-dependent 36Cl- influx was produced by the convulsant drugs, bicuculline, picrotoxin, and pentylenetetrazole. Ion specificity was demonstrated by a failure of GABA agonists to stimulate influx of 45Ca2+, 86Rb+, 22Na+, or 35SO4(2). GABA-stimulated uptake of 36Cl- was largest in cortex and cerebellum and smaller in hippocampus and striatum. There was little difference in sensitivity to GABA among the areas. Analysis of subcellular fractions prepared from mouse brain demonstrated that the GABA-dependent 36Cl- influx was enriched in the synaptosomal fraction. The nonspecific (GABA-independent) uptake of 36Cl- was enriched in the myelin fraction. These experiments provide evidence for a functional coupling among GABA receptors and the chloride ionophore and suggest that the GABA-activated chloride channel is a site of action for several convulsant compounds.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1997

A protein factor that inhibits ATP-dependent glutamate and gamma-aminobutyric acid accumulation into synaptic vesicles: purification and initial characterization.

Glutamate, the major excitatory neurotransmitter in the mammalian central nervous system, is transported into and stored in synaptic vesicles. We have purified to apparent homogeneity a protein from brain cytosol that inhibits glutamate and gamma-aminobutyric acid uptake into synaptic vesicles and have termed this protein "inhibitory protein factor" (IPF). IPF refers to three distinct proteins with relative molecular weights of 138,000 (IPF alpha), 135,000 (IPF beta), and 132,000 (IPF gamma), respectively. Gel filtration and sedimentation data suggest that all three proteins share an elongated structure, identical Stokes radius (60 A), and identical sedimentation coefficient (4.3 S). Using these values and a partial specific volume of 0.716 ml/g, we determined the native molecular weight for IPF alpha to be 103,000. Partial sequence analysis shows that IPF alpha is derived from alpha fodrin, a protein implicated in several diverse cellular activities. IPF alpha inhibits ATP-dependent glutamate uptake into purified synaptic vesicles with an IC50 of approximately 26 nM, while showing no ability to inhibit ATP-independent uptake at concentrations up to 100 nM. Moreover, IPF alpha inhibited neither norepinephrine uptake into chromaffin vesicles nor Na+-dependent glutamate uptake into synaptosomes. However, IPF alpha inhibited uptake of gamma-aminobutyric acid into synaptic vesicles derived from spinal cord, suggesting that inhibition may not be limited to glutamatergic systems. We propose that IPF could be a novel component of a presynaptic regulatory system. Such a system might modulate neurotransmitter accumulation into synaptic vesicles and thus regulate the overall efficacy of neurotransmission.

Adenosine Triphosphate↗
PubMed1998

Systemic gabapentin and S(+)-3-isobutyl-gamma-aminobutyric acid block secondary hyperalgesia.

Gabapentin (GBP) and S(+)-3-isobutyl-gamma-aminobutyric acid (IBG) are anticonvulsant agents which are effective against many clinical and experimental neuropathic pain states. We examined the efficacy of these agents in a new rat model of secondary mechanical hyperalgesia generated by a mild thermal injury. Under brief halothane anesthesia, an injury was induced by applying one heel to a hot surface (52.5 degreesC) for 45 s. GBP, IBG or saline was injected i.p. just prior to the injury. Mean mechanical withdrawal threshold (MWT) was determined using von Frey hairs before and at 30 min intervals for 3 h following the injury. MWT outside the injury area decreased post-injury (secondary hyperalgesia, allodynia), but primary (site of injury) mechanical hyperalgesia was not observed. Secondary hyperalgesia exhibited a tendency toward recovery over time. Time to onset of the anti-allodynic effect of GBP was 30-60 min. The minimum effective GBP dose was 100 mg/kg; 300 mg/kg GBP totally inhibited the drop in MWT, but was accompanied by pronounced sedation. Anti-allodynic effects of IBG were apparent at the first post-injury measure of MWT (30 min). Thirty milligrams per kilogram was the minimum effective dose; 100 mg/kg IBG totally blocked the allodynia with minimal side effects. Our findings demonstrate a dose-dependent blockade of the mechanical sensitivity caused by a mild thermal injury by both GBP and IBG. Results indicate that IBG is more effective than GBP in this model at doses which do not cause sedation. These observations support the suggested use of these or related gamma-amino acid analogues as an effective treatment for post-operative pain.

Acetates↗
PubMed1998

Association between the gamma-aminobutyric acid A3 receptor gene and multiple sclerosis.

BACKGROUND: In a prior study we observed an association between the dopamine D2 receptor gene (DRD2) and the age of onset and/or diagnosis of multiple sclerosis (MS). We hypothesized that this effect was mediated through the dopaminergic control of the release of prolactin, a modulator of immune response. Since gamma-aminobutyric acid also modulates the release of prolactin, we examined the possible association between alleles of the GABRA3 (gamma-aminobutyric acid A3 receptor) gene and MS. DESIGN: We examined the GABRA3 alleles of 189 subjects with MS who died of their disease. They were divided into test group 1 (n=64) and retest group 2 (n=56). Each group had a separate set of controls (group 1, n=109; group 2, n=430). All subjects were white. All were tested at a dinucleotide cytosine-adenosine repeat polymorphism with 6 alleles representing 11 to 16 repeats. RESULTS: In the first group there was a significant difference in the frequency of the GABRA3 alleles (P<.002), with the most notable difference being an increase in the frequency of the 16-repeat allele in subjects with MS and a relative decrease in the other alleles. In the replication group there was again a significant difference in the distribution of the GABRA3 alleles (P<.001), and again the greatest difference was an increase in the frequency of the 16-repeat allele in subjects with MS. For both groups combined, a significant difference in the frequency of the 16-repeat allele was noted (chi2=46.30; P<.001). CONCLUSIONS: These results suggest the GABRA3 gene may be a risk factor for MS. As with the DRD2 gene, the effect may be mediated through its regulation of prolactin release.

Alleles↗