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At least 325 records · Page 18Linked to original sources
PubMed1964

NONSPECIFIC DEPRESSANT ACTION OF GAMMA-AMINOBUTYRIC ACID ON SOMATIC REFLEXES.

The effects of gamma-aminobutyric acid (GABA) on central integration of somatic reflexes in the cat have been studied by topical application, and by intrathecal or intracerebroventricular injection. Intrathecal injection of GABA inhibited the monosynaptic patellar reflex. The facilitation of the patellar reflex induced by strychnine, leptazol, tubocurarine and tetanus toxin was also inhibited. Polysynaptic facilitation of the patellar reflex induced in the spinal cat by electrical stimulation of the contralateral sciatic nerve was depressed by intrathecal GABA. Similarly, the supraspinal facilitation of the patellar reflex by electrical stimulation of the brain stem reticular formation was inhibited by application of GABA to the floor of the 4th ventricle. The polysynaptic inhibition of the patellar reflex at both levels was intensified by GABA. The flexor (tibialis anterior) reflex was depressed in the same manner as the extensor patellar reflex. The polysynaptic linguomandibular reflex was depressed by intracerebroventricular GABA. The depressant action of GABA at spinal and supraspinal levels of the neuraxis is discussed in relation to the role of GABA as an inhibitory transmitter in the central nervous system.

Aminobutyrates↗
PubMed1994

Inhibition of neonatal brain fuel utilization by valproate and E-delta 2-valproate is not a consequence of the stimulation of the gamma-aminobutyric acid shunt.

Stimulation of the gamma-aminobutyric acid (GABA) shunt by valproate and its major metabolite, E-delta 2-valproate, has been proposed to decrease brain energy metabolism. In order to elucidate this hypothesis, the effect of these drugs on substrate utilization in neonatal rat brain slices was studied. The overall rate of lactate utilization was dose-dependently inhibited by both drugs. Valproate and E-delta 2-valproate inhibited both sterol and fatty acid syntheses from 3-hydroxybutyrate. The rate of glucose utilization was not affected by valproate nor E-delta 2-valproate. The inhibition of the GABA aminotransferase by aminooxyacetate decreased lipogenesis from lactate, 3-hydroxybutyrate and glucose. The inhibitor of the mitochondrial pyruvate carrier, alpha-cyano-4-hydroxycinnamate, strongly decreased the rate of lactate, 3-hydroxybutyrate and glucose utilization, suggesting that the inhibition of pyruvate mitochondrial carrier is not the mode of action of these drugs. It is suggested that inhibition of plasma membrane monocarboxylate carrier by valproate and E-delta 2-valproate, but not the activation of the GABA shunt, is responsible for the inhibition of the brain fuel utilization.

Animals↗
PubMed1984

Efflux of gamma-aminobutyric acid from and appearance of free arachidonic acid inside synaptosomes.

When synaptosomes were depolarized in the presence of Ca2+, or when Ca2+ was added to synaptosomes pretreated with Ca2+ ionophore (A23187), free arachidonic acid was clearly increased within synaptosomes, and at the same time an efflux of gamma-aminobutyric acid from synaptosomes was observed. Moreover, when synaptosomes labelled with [14C]arachidonic acid were depolarized in the presence of Ca2+, there was a significant decrease in the radioactivity of the fatty acid of phosphatidylinositol and phosphatidylcholine. Exogenously added arachidonic acid, but not other fatty acids, stimulated the efflux of gamma-aminobutyric acid in the absence of Ca2+. These observations suggest that the release of arachidonic acid from phospholipids is an intrinsic part of the biochemical mechanism that modulates the gamma-aminobutyric acid efflux.

Animals↗
PubMed1998

Characterization of the effects of gabapentin and 3-isobutyl-gamma-aminobutyric acid on substance P-induced thermal hyperalgesia.

BACKGROUND: The authors sought to characterize the pharmacologic characteristic and site of action of gabapentin (Neurontin) in a model of thermal hyperalgesia induced by intrathecal substance P administration. METHODS: Rats were prepared with long-term lumbar intrathecal catheters. Hind paw withdrawal latency was determined using a radiant heat stimulus focused through a glass surface onto the plantar surface of the paw. RESULTS: Within 5 min after intrathecal injection of substance P (30 nmol), hind paw withdrawal latency fell from 11 to 8 s. Gabapentin given intrathecally or intraperitoneally produced dose-dependent reversal of the thermal hyperalgesia, with complete reversal (ED100) occurring at 163 microg for intrathecal and 185 mg/kg for intraperitoneal administration. S(+)-3-isobutyl-gamma aminobutyric acid, but not R(-)-3-isobutyl-gamma aminobutyric acid, also produced dose-dependent reversal of the intrathecal substance P-induced thermal hyperalgesia (intrathecal ED100, 65 microg and intraperitonal ED100, 31 mg/kg). The effects of intraperitoneally administered gabapentin and 3-isobutyl-gamma aminobutyric acid were reversed by intrathecal pretreatment with D-serine (100 microg) but not by L-serine. All effects were observed at doses that had little effect on motor function or spontaneous activity. Intrathecal N-methyl-D-aspartate (2 nmol) induced thermal hyperalgesia, which was blocked by gabapentin (100 mg/kg intraperitoneally) and S(+)-3-isobutyl-gamma aminobutyric acid (30 mg/kg intraperitoneally). CONCLUSIONS: The structure-activity relationship and the stereospecificity noted after intrathecal delivery suggest that gabapentin and S(+)-3-isobutyl-gamma aminobutyric acid act at a common spinal locus to modulate selectively a facilitated state of nociceptive processing.

Acetates↗
PubMed1986

Effect of centrally administered gamma-aminobutyric acid on metabolic function.

gamma-Aminobutyric acid (GABA) content of the brain increases during hypoxia and hypercapnia and GABA by itself is a central ventilatory depressant and may depress metabolism as well. Therefore the effect of centrally administered GABA by ventriculocisternal perfusion on O2 consumption (VO2) and CO2 production (VCO2) was studied in pentobarbital-anesthetized dogs. GABA (30 mM) in mock cerebrospinal fluid (CSF) was perfused for 15 min at the rate of 1.0 ml/min followed by perfusion with mock CSF alone. Body temperature, perfusion pressure, and CSF pH were kept constant. Minute ventilation (VE) was kept constant mechanically. Under these conditions, VO2, VCO2, alveolar ventilation (VA), and relative pulmonary dead space volume (VD/VT) were measured. During perfusion with 30 mM GABA, mean VO2 (+/- SE) decreased from 96.5 +/- 3.3 to 81.9 +/- 5.1 ml/min, VCO2 from 72.1 +/- 3.8 to 60.7 +/- 3.0 ml/min, and VA from 1.7 +/- 0.1 to 1.3 +/- 0.1 l/min. VD/VT increased from 0.55 +/- 0.02 to 0.65 +/- 0.01. Perfusion with mock CSF alone restored these parameters to initial levels within 15 min. We conclude that centrally administered GABA depresses VO2 and VCO2. This reduction in metabolic function is independent of the central modulatory effects of GABA on respiration.

Acid-Base Equilibrium↗
PubMed1995

Short external loops as potential substrate binding site of gamma-aminobutyric acid transporters.

While the gamma-aminobutyric acid (GABA) transporter GAT1 exclusively transports GABA, GAT2, -3, and -4 also transport beta-alanine. Cross-mutations in the external loops IV, V, and VI among the various GABA transporters were performed by site-directed mutagenesis. The affinity of GABA transport as well as inhibitor sensitivity of the modified transporters was analyzed. Kinetic analysis revealed that a cross-mutation in which loop IV of GAT1 was modified to resemble GAT4 resulted in increased affinity to GABA from Km = 8.7 to 2.0 microM without changing the Vmax. A cross-mutation in loop VI, which swapped the amino acid sequence of GAT2 for GAT1, decreased the affinity to GABA (Km, 35 microM). These results suggest that loops IV and VI contribute to the binding affinity of GABA transporters. A substitution of three amino acids in loop V of GAT1 by the corresponding sequence of GAT3 resulted in beta-alanine sensitivity of its GABA uptake activity. These three amino acids in loop V seem to participate in the beta-alanine binding domain of GAT3. It is suggested that those three external loops (IV, V, and VI) form a pocket in which the substrate binds to the GABA transporters.

Amino Acid Sequence↗
PubMed1975

Cerebrospinal fluid gamma aminobutyric acid levels in migraine.

Gamma-Aminobutyric acid (GABA) levels in cerebrospinal fluid were measured in seven patients with tension headache and 12 patients with migraine. GABA was detected only during the migraine attack. The results suggest disordered GABA metabolism in migraine.

Aminobutyrates↗
PubMed1979

Depolarization of neurones in the isolated olfactory cortex of the guinea-pig by gamma-aminobutyric acid.

1 Effects of gamma-aminobutyric acid (GABA) on single neurones in slices of guinea-pig olfactory cortex maintained in vitro were recorded with single intracellular microelectrodes. The average resting potential of 52 cells was -75 mV and apparent input resistance ranged from 20 to 200 MOmega.2 Superfusions of GABA over the slice invariably depolarized the neurones and reduced their input resistance. The minimum effective concentration was 50 to 200 muM.3 The reversal potential for the depolarization produced by 0.1 mM GABA (E(g)) was -66 +/- 2 mV. At concentrations >0.1 mM the reversal potential became progressively more positive (-55 to -50 mV).4 Reduction of external chloride, with isethionate as the substitute anion, increased the amplitude of the depolarization.5 GABA reduced the amplitude of the excitatory postsynaptic potential produced by lateral olfactory tract stimulation, and occluded or reversed the subsequent depolarizing recurrent inhibitory postsynaptic potential.6 Action potentials elicited by injection of depolarizing current or by focal antidromic stimulation were slowed and reduced in amplitude by GABA.7 The effects of GABA on membrane conductance (potency = 1) were duplicated by 3-aminopropanesulphonic acid (potency = 20), beta-alanine (0.5), beta-amino-n-butyric acid (0.5), glycine (0.3) and L-2,4-diaminobutyric acid (0.2). For a given conductance change, 3-aminopropanesulphonic acid, glycine and beta-alanine produced less depolarization than did GABA.8 It is concluded that the action of GABA on the neurones is compatible with a role in mediating recurrent postsynaptic inhibition.

Action Potentials↗
PubMed1989

The effect of monoamine depletors on metrazol induced convulsions and brain gamma-aminobutyric acid (GABA) contents in rats.

The thresholds for metrazol (pentylenetetrazol) clonic convulsions and brain gamma-aminobutyric acid contents were significantly reduced after treatment with the monoamine depletors reserpine, tetrabenazine and p-chlorophenylalanine. Moreover, alpha-methyltyrosine, and alpha-methyl-m-tyrosine also lowered metrazol threshold seizures, but had no effect on brain alpha-aminobutyric acid contents. Furthermore, neither 5-hydroxytryptophan nor tranylcypromine had a significant effect on metrazol threshold seizures or brain alpha-aminobutyric acid contents, but blocked the changes previously induced by p-chlorophenyl alanine and reserpine.

Animals↗
PubMed1985

Inhibition of 4-aminobutyric acid (GABA) turnover by chlordane.

4-Aminobutyric acid (GABA) turnover was measured in mice 8 h after an acute injection of 1 g/kg of technical grade chlordane in corn oil. Significant decreases in GABA turnover were observed in the cortex, striatum, hippocampus and hypothalamus after chlordane treatment. A smaller, though significant, decrease was also observed in the cerebellum. These results may help to explain the hyperexcitability and convulsions observed after acute high-dose exposure to this compound.

Animals↗
PubMed1986

Isothiouronium compounds as gamma-aminobutyric acid agonists.

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.

4-Aminobutyrate Transaminase↗
PubMed1991

Pergolide presynaptically inhibits calcium-stimulated release of gamma-aminobutyric acid.

The release of gamma-aminobutyric acid (GABA) in rat dorsolateral striatum was studied using in vivo microdialysis. Dialysis was conducted 2 days after probe implantation in awake, freely moving rats using a modified Ringer solution. Calcium induced a reversible increase in GABA release that was abolished by tetrodotoxin but was only slightly attenuated by a maximally effective dose of pergolide, a D2 receptor agonist. It was thus concluded that pergolide inhibits calcium-stimulated release of GABA presynaptically by a mechanism distinct from that of tetrodotoxin.

Animals↗
PubMed1993

[Gamma-aminobutyric acid and glutamate decarboxylase].

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the CNS, taking part in processes which are now relatively well understood but also in processes which are remarkable progress has been achieved. The most thoroughly studied field of GABA operation is its role of inhibitory neurotransmitter realized through the mediation of GABA-A and GABA-B receptors. There are at least 40 per cent of synaptic inhibitory events in the CNS in which the neurotransmitter action of GABA is involved. The action of GABA on GABA-A receptor, a Cl- channel, is influenced by benzodiazepines, barbiturates and other substances, suggesting that some neurological and psychiatric diseases are connected with the function of GABA-A receptor. In addition to synaptic inhibition, GABA has several metabolic regulatory functions. GABA is produced not only in neurons but also in beta cells of the pancreas and in tubular cells of the kidney cortex. Its role in these parenchymatous cells is not sufficiently understood. Similarly as GABA, glutamic acid decarboxylase (GAD), an enzyme catalysing GABA formation from glutamate, has also been intensively studied. GAD structure, its function in various parts of the CNS and in some parenchymatous cells, and the regulation of GAD activity are still in the focus of interest. Recently GAD has been demonstrated to act as autoantigen in the rare neurological disease "stiff man syndrome" (SMS) and in insulin-dependent diabetes mellitus (IDDM). In the presented paper a short review of GABA functions, GAD properties and of the antigenic feature of GAD are given. (Fig. 7, Ref. 41.)

Animals↗
PubMed1993

Only one of the charged amino acids located in the transmembrane alpha-helices of the gamma-aminobutyric acid transporter (subtype A) is essential for its activity.

The gamma-aminobutyric acid (GABA) transporter (subtype A) is located in nerve terminals and catalyses coupled electrogenic uptake of the neurotransmitter with two or three sodium and one chloride ions. It contains 599 amino acids and 12 putative membrane spanning alpha-helices and is the first described member of a neurotransmitter transporter superfamily. The membrane domain contains 5 charged amino acids which are basically conserved. Using site-directed mutagenesis, we show that only one of them, arginine 69, is absolutely essential for activity. It is located in a highly conserved region encompassing parts of helices 1 and 2. The three other positively charged amino acids and the only negative charged one, glutamate 467, are not critical. These results suggest that the translocation pathway of the sodium ions through the membrane does not involve charged amino acid residues and underline the importance of the highly conserved stretch between amino acids 66 and 86.

Base Sequence↗
PubMed1982

Protection from local anesthetic-induced convulsions by gamma-aminobutyric acid.

The effects of gamma-aminobutyric acid (GABA) on the induction of convulsions by local anesthetics were investigated in mice and rats. Intraventricular administration of 0.8-1.6 mg GABA protected rats against convulsions induced by procaine, lidocaine, cocaine, and tetracaine in a dose-related manner. Intraperitoneal gamma-acetylenic GABA was also effective against procaine-induced convulsions in mice, but the metabolites of GABA, gamma-hydroxybutyrate, and gamma-butyrolactone were without effect. Intraventricular GABA, 1.6 mg, delayed the onset of convulsions induced by hydrazine, but had no influence on the incidence of convulsions induced by nicotine, pentylenetetrazol, picrotoxin, or strychnine. These results suggest that the GABA system may be involved in the mechanisms of local anesthetic-induced convulsions.

Anesthetics, Local↗
PubMed1993

Gamma-aminobutyric acid and the liver.

Gamma-aminobutyric acid (GABA) is a potent amino acid neurotransmitter with various physiologic effects throughout the body. Over the past 40 years it has become evident that the mammalian liver contains high concentrations of GABA which are carefully regulated by a series of hepatic metabolic pathways and a specific sodium-dependent active transport system. It is also clear that the liver possesses sodium-independent, bicuculline-sensitive GABAA receptor sites which when innervated cause marked hyperpolarization of the hepatocyte transmembrane potential. Recent data suggest that extensive hepatic injury alters GABA homeostatic mechanisms which in turn may contribute to the pathogenesis of hepatic encephalopathy and systemic hypotension. There is also reason to believe that increased GABAergic activity may inhibit hepatic regeneration following partial hepatectomy in rats.

Animals↗