Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers.
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Vigabatrin increases gamma aminobutyric acid (GABA) levels by irreversible inhibition of the GABA-catabolizing enzyme GABA-transaminase (GABA-T). Preclinical studies suggest anxiolytic effects in vigabatrin treated rats. Anxiolytic effects in patients with panic disorder (PD) could therefore be expected. To evaluate putative anxiolytic properties of vigabatrin in humans, CCK-4-induced panic symptoms were studied in healthy volunteers before and after vigabatrin treatment. After placebo-controlled administration of 50 microg CCK-4, ten healthy volunteers received vigabatrin for seven days with a daily dosage of 2 g. The treatment period was followed by a second CCK-4 challenge. Panic and anxiety were assessed using the Acute Panic Inventory (API) score and a DSM-IV derived panic-symptom-scale (PSS). ACTH and cortisol plasma levels were determined during the CCK-4 challenge. All subjects reported a marked reduction of CCK-4-induced panic symptoms and anxiety after seven days of vigabatrin treatment both in the API- and PSS-scores. Moreover, there was a significant attenuation of CCK-induced elevation of ACTH and cortisol levels following vigabatrin treatment. In conclusion, our data show that GABA-transaminase inhibitors exert anxiolytic effects in CCK-4-induced panic in healthy volunteers and suggest that GABA transaminase inhibitors might be useful in ameliorating panic symptoms also in patients with PD. (+info)
The Rhizobium leguminosarum bv. viciae VF39 gamma-aminobutyrate (GABA) aminotransferase gene (gabT) is induced by GABA and highly expressed in bacteroids.
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A Rhizobium leguminosarum bv. viciae VF39 gene (gabT) encoding a gamma-aminobutyrate (GABA) aminotransferase was identified, cloned and characterized. This gene is thought to be involved in GABA metabolism via the GABA shunt pathway, a theoretical bypass of the 2-oxoglutarate dehydrogenase complex. Mutants in gabT are still able to grow on GABA as a sole carbon and nitrogen source. 2-oxoglutarate-dependent GABA aminotransferase activity is absent in these mutants, while pyruvate-dependent activity remains unaffected. This indicates that at least two enzymes with different substrate specifities are involved in the GABA metabolism of R. leguminosarum bv. viciae VF39. The gabT promoter was cloned into a newly constructed, stable promoter-probe vector pJP2, suitable for the study of transcriptional GUS fusions in free-living bacteria and during symbiosis. Under free-living conditions the gabT promoter is induced by GABA and repressed by succinate. Transcriptional regulation is mediated by GabR in a repressor-like manner. During symbiosis with the pea host plant gabT is induced and highly expressed in the symbiotic zone. Nodules induced by gabT mutants, however, are still effective in nitrogen fixation. (+info)
Drug addiction. Part III. Pharmacotherapy of addiction.
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The last decade brought a considerable progress in pharmacotherapy of addiction. Basing on recently gained knowledge of mechanisms of development of addiction and the physiology of the brain reward system, several therapeutic strategies have evolved. The strategies aimed at targeting the basic mechanisms of addiction rely on the premises that addiction is caused by adaptive changes in the central nervous system and that craving, which is the main cause of relapse, depends on dopaminergic mechanisms and requires high general excitability. The pharmacological approach involves drugs that reduce neuronal adaptability by inhibiting the calcium entry to neurons both through voltage-gated channels (e.g. nimodipine) and NMDA receptors (e.g. memantine), and drugs that stimulate the inhibitory GABAergic system (gamma-vinyl-GABA, baclofen), Particular attention is paid to the compounds that may attenuate dopaminergic hyperactivity, without considerable suppression of tonic activity of dopaminergic neurons (e.g. BP 897, a partial dopamine D3 receptor antagonist). Specific strategies are aimed at interference with the action of particular drugs of addiction. An important group includes the agonistic therapies (known also as substitution or maintenance therapies) in which a long-acting agonist is used in order to reduce the action of the drugs of high addictive potential (e.g. methadone against heroin addiction or vanoxerine (GBR 12909) against psychostimulants). Other specific strategies aimed at reduction of the transport of molecules of addictive substances into the brain: the approaches involve preparation of antibodies that form complexes unable to cross blood-brain barrier or enzymes accelerating the metabolism of the compounds in the blood (e.g. variants of butyrylcholinesterase). A considerable progress has been made in combating the abuse of legal addictive substances, alcohol (naltrexone, acamprosate) and tobacco (bupropion). The prospects for developing effective pharmacotherapies against addiction are bright. Unfortunately, ideological and social implications, as well as the conflict of interest with illegal narcotic manufacturers and distributors, may considerably hamper the progress in combating addiction (e.g. difficulties in introduction of methadone). (+info)
4-aminobutyrate in mammalian putrescine catabolism.
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The effects of inhibitors of diamine oxidase (EC 1.4.3.6), monoamine oxidase (EC 1.4.3.4) and 4-aminobutyrate aminotransferase (EC 2.6.1.19) on the catabolism of putrescine in mice in vivo were studied. Diamine oxidase inhibitors and carboxymethoxylamine (amino-oxyacetate) markedly inhibit the metabolism of [(14)C]putrescine to (14)CO(2), but affect different enzymes. Aminoguanidine specifically inhibits the mitochondrial and non-mitochondrial diamine oxidases, whereas carboxymethoxylamine specifically inhibits 4-aminobutyrate transamination by the mitochondrial pathway. Hydrazine inhibits at both sites, and results in increased concentrations of 4-aminobutyrate in brain and liver. Pretreatment of mice with carboxymethoxylamine and [(14)C]putrescine leads to the urinary excretion of amino[(14)C]butyrate. Carboxymethoxylamine does not affect the non-mitochondrial pathway of putrescine catabolism, as the product of oxidative deamination of putrescine in the extramitochondrial compartment is not further oxidized but is excreted in the urine as derivatives of 4-aminobutyraldehyde. Another catabolic pathway of putrescine involves monoamine oxidase, and the monoamine oxidase inhibitor, pargyline, decreases the metabolism of [(14)C]putrescine to (14)CO(2)in vivo. Catabolism of putrescine to CO(2)in vivo occurs along different pathways, both of which have 4-aminobutyrate as a common intermediate, in contrast with the non-mitochondrial catabolism of putrescine, which terminates in the excretion of 4-aminobutyraldehyde derivatives. The significance of the different pathways is discussed. (+info)
Subcellular localization of gamma-aminobutyrate transaminase and glutamate dehydrogenase in adult rat brain. Evidence for at least two small glutamate compartments in brain.
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The subcellular localizations of gamma-aminobutyrate transaminase (EC 2.6.1.19) and glutamate dehydrogenase (EC 1.4.1.2) in brain tissue of adult rats were compared with each other and with those of NAD+-isocitrate dehydrogenase (EC 1.1.41) and monoamine oxidase (EC 1.4.3.4; kynuramine as substrate). Crude mitochondrial fractions from brain tissue were centrifuged in continuous sucrose density gradients. gamma-Aminobutyrate transaminase and glutamate dehydrogenase were always found at a higher density than NAD+-isocitrate dehydrogenase and monoamine oxidase. When centrifuged for 1 h at 53 000gav., there was a slight difference between the distribution profiles of glutamate dehydrogenase and gamma-aminobutyrate transaminase. This difference was larger when the centrifugation time was only 15 min. It is concluded that there are subpopulations of brain mitochondria with differing proportions of gamma-aminobutyrate transaminase and glutamate dehydrogenase. The results are discussed in relation to evidence obtained with labelled precursors in vivo that there are at least two small glutamate compartments in adult brain. (+info)
The Escherichia coli gabDTPC operon: specific gamma-aminobutyrate catabolism and nonspecific induction.
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Nitrogen limitation induces the nitrogen-regulated (Ntr) response, which includes proteins that assimilate ammonia and scavenge nitrogen. Nitrogen limitation also induces catabolic pathways that degrade four metabolically related compounds: putrescine, arginine, ornithine, and gamma-aminobutyrate (GABA). We analyzed the structure, function, and regulation of the gab operon, whose products degrade GABA, a proposed intermediate in putrescine catabolism. We showed that the gabDTPC gene cluster constitutes an operon based partially on coregulation of GabT and GabD activities and the polarity of an insertion in gabT on gabC. A DeltagabDT mutant grew normally on all of the nitrogen sources tested except GABA. The unexpected growth with putrescine resulted from specific induction of gab-independent enzymes. Nac was required for gab transcription in vivo and in vitro. Ntr induction did not require GABA, but various nitrogen sources did not induce enzyme activity equally. A gabC (formerly ygaE) mutant grew faster with GABA and had elevated levels of gab operon products, which suggests that GabC is a repressor. GabC is proposed to reduce nitrogen source-specific modulation of expression. Unlike a wild-type strain, a gabC mutant utilized GABA as a carbon source and such growth required sigma(S). Previous studies showing sigma(S)-dependent gab expression in stationary phase involved gabC mutants, which suggests that such expression does not occur in wild-type strains. The seemingly narrow catabolic function of the gab operon is contrasted with the nonspecific (nitrogen source-independent) induction. We propose that the gab operon and the Ntr response itself contribute to putrescine and polyamine homeostasis. (+info)
Anacystis nidulans mutants resistant to aromatic amino acid analogues.
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Three classes of mutants of Anacystis nidulans were selected on the basis of resistance to fluorophenylalanine and 2-amino-3-phenylbutanoic acid. The most frequent type exhibited DAHP synthetase (7-phospho-2-keto-3-deoxy-D-arabino-heptonate-D-erythrose-4-phosphate-lyase [pyruvate phosphorylating], EC 4.1.2.15) activity identical to that of the parental strain. The second type was characterized by extremely low levels of the activity. The third type had a DAHP synthetase showing decreased sensitivity to inhibition by L-tyrosine. The enzyme was purified 140-fold from wild-type and feedback-insensitive strains, and the kinetics of the reaction was examined. The activity of the wild-type enzyme was inhibited 75% in the presence of 2.0 X 10-3 M tyrosine, and the altered enzyme was inhibited 10%. The following apparent constants were obtained from kinetic studies with partially purified wild-type enzyme: S0.5 for D-erythrose-4-phophate equal to 7.1 X 10-4 M; S0.5 for phosphoenolpyruvate equal to 1.4 X 10-4 M. Inhibition by tyrosine was mixed with respect to binding of both D-erythrose-4-phosphate and phosphoenolpyruvate. In addition, tyrosine promoted cooperative interactions in the binding of phosphoenolpyruvate. For the altered enzyme the following apparent constants were obtained: S0.5 for D-erythrose-4-phosphate equal to 7.1 X 10-4 M; S0.5 for phosphoenolpyruvate equal to 2.9 X 10-4 M. Inhibition by tyrosine was mixed with respect to D-erythrose-4-phosphate and competitive with respect to phosphoenolpyruvate. Tyrosine did not promote cooperative effects in the binding of phosphoenolpyruvate to the altered enzyme. (+info)
Dietary protein restriction causes modification in aluminum-induced alteration in glutamate and GABA system of rat brain.
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BACKGROUND: Alteration of glutamate and gamma-aminobutyrate system have been reported to be associated with neurodegenerative disorders and have been postulated to be involved in aluminum-induced neurotoxicity as well. Aluminum, an well known and commonly exposed neurotoxin, was found to alter glutamate and gamma-aminobutyrate levels as well as activities of associated enzymes with regional specificity. Protein malnutrition also reported to alter glutamate level and some of its metabolic enzymes. Thus the region-wise study of levels of brain glutamate and gamma-aminobutyrate system in protein adequacy and inadequacy may be worthwhile to understand the mechanism of aluminum-induced neurotoxicity. RESULTS: Protein restriction does not have any significant impact on regional aluminum and gamma-aminobutyrate contents of rat brain. Significant interaction of dietary protein restriction and aluminum intoxication to alter regional brain glutamate level was observed in the tested brain regions except cerebellum. Alteration in glutamate alpha-decarboxylase and gamma-aminobutyrate transaminase activities were found to be significantly influenced by interaction of aluminum intoxication and dietary protein restriction in all the tested brain regions. In case of regional brain succinic semialdehyde content, this interaction was significant only in cerebrum and thalamic area. CONCLUSION: The alterations of regional brain glutamate and gamma-aminobutyrate levels by aluminum are region specific as well as dependent on dietary protein intake. The impact of aluminum exposure on the metabolism of these amino acid neurotransmitters are also influenced by dietary protein level. Thus, modification of dietary protein level or manipulation of the brain amino acid homeostasis by any other means may be an useful tool to find out a path to restrict amino acid neurotransmitter alterations in aluminum-associated neurodisorders. (+info)