Summary
Pretreatment of rats with aminooxyacetic acid (AOAA; 40 mg/kg) raised the concentration of rat brain GABA and inhibited the hyperactivity produced by increasing brain 5-hydroxytryptamine (5-HT) concentration by administration of tranylcypromine and L-tryptophan. The maximum effect was seen 90 min after AOAA injection with smaller effects 30 and 180 min after injection. AOAA did not affect the rate of 5-HT accumulation in the brain, but did inhibit the hyperactivity response which follows injection of the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine, suggesting that post-synaptic 5-HT responses were being inhibited.
AOAA also inhibited the locomotor activity which follows administration of tranylcypromine and L-dopa. Blockade of GABA receptors by injection of picrotoxin (2.5 mg/kg) enhanced the dopamine hyperactivity. Since a dopaminergic system has been shown to be involved in the 5-HT hyperactivity syndrome and appears to act post-synaptically to the 5-HT neurones initiating the syndrome it is suggested that inhibition of the 5-HT hyperactivity syndrome may be due to accumulation of GABA distal to the dopaminergic receptors.
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Andén, N.-E.: Inhibition of the turnover of the brain dopamine after treatment with the gamma-amino butyrate: 2-oxyglutarate transaminase inhibitor aminooxyacetic acid. Naunyn-Schmiedeberg's Arch. Pharmac.283, 419–424 (1974).
Andén, N.-E., Stock, G.: Inhibitory effect of gamma hydroxy butyric acid and gamma-amino butyric acid on the dopamine cells in the substantia nigra. Naunyn-Schmiedeberg's Arch. Pharmac.297, 89–92 (1973).
Balázs, R., Machiyama, Y., Hammond, B. J., Julian, T., Richter, D.: The operation of theγ-amino butyrate bypath of the tricarboxylic acid cycle in brain tissue in vitro. Biochem. J.116, 445–461 (1970).
Chang, C. C.: A sensitive method for spectrophotofluorometric assay of catecholamines. Int. J. Neuropharmac.3, 643–649 (1964).
Collins, G. G. S.: GABA-2 oxoglutarate transaminase, glutamate decarboxylase and the half life of GABA in different areas of rat brain. Biochem. Pharmac.21, 2849–2858 (1972).
Curzon, G., Green, A. R.: Rapid method for the determination of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in small regions of rat brain. Br. J. Pharmac.39, 653–655 (1970).
Fuxe, K., Hökfelt, T., Ljungdahl, Å., Agnati, L., Johansson, O., Perez de la Mora, M.: Evidence for an inhibitory gabergic control of the mesolimbic dopamine neurones: possibility of improving treatment of schizophrenia by combined treatment with neuroleptics and gabergic drugs. Med. Biol.53, 177–183 (1975).
Garfinkel, D.: A simulation study of brain compartments. 1. Fuel sources of GABA metabolism. Brain Res.23, 387–406 (1970).
Grahame-Smith, D. G.: Studiesin vivo on the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan. J. Neurochem.18, 1053–1066 (1971 a).
Grahame-Smith, D. G.: Inhibitory effect of chlorpromazine on the syndrome of hyperactivity produced by L-tryptophan or 5-methoxy-N,N-dimethyltryptamine in rats treated with a monoamine oxidase inhibitor. Br. J. Pharmac.43, 856–864 (1971 b).
Green, A. R., Grahame-Smith, D. G.: The role of brain dopamine in the hyperactivity syndrome produced by increased 5-hydroxytryptatmine synthesis in rats. Neuropharmacology13, 949–959 (1974).
Green, A. R., Grahame-Smith, D. G.: The effects of drugs on the processes regulating the functional activity of brain 5-hydroxytryptamine. Nature (London). In Press (1976).
Green, A. R., Youdim, M. B. H., Grahame-Smith, D. G.: Quipazine: its effects on rat brain 5-hydroxytryptamine metabolism, monoamine oxidase activity and behaviour. Neuropharmacology. In Press (1976).
Hammond, B. J., Julian, T., Machiyama, Y., Balázs, R.: Mathematical approaches to the evaluation of the flux ofγ-aminobutyrate in brain tissuein vitro. Biochem. J.116, 445–467 (1970).
Jacoby, W. B., Scott, E. M.: Aldehyde oxidation. iii. Succinic semialdehyde dehydrogenase. J. Biol. Chem.234, 937–940 (1959).
Kim, J. S., Bak, I. J., Hassler, R., Okuda, Y.: Role ofγ-amino butyric acid (GABA) in the extrapyramidal motor system. 2. Some evidence for the existence of a type of GABA-rich strionigral neurons. Exp. Brain Res.14, 95–104 (1971).
Kravitz, E. A., Potter, D. D.: A further study of the distribution ofγ-aminobutyric acid between excitatory and inhibitory axons of the lobster. J. Neurochem.12, 323–328 (1965).
Kuriyama, K., Roberts, E., Rubinstein, M. K.: Elevation ofγ-aminobutyric acid in brain with amino-oxyacetic acid and susceptibility to convulsive seizures in mice: a quantitative re-evaluation. Biochem. Pharmac.15, 221–236 (1966).
Roberts, E.:γ-aminobutyric acid and nervous system function—a perspective. Biochem. Pharmac.23, 2637–2649 (1974).
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Green, A.R., Tordoff, A.F.C. & Bloomfield, M.R. Elevation of brain GABA concentrations with amino-oxyacetic acid; effect on the hyperactivity syndrome produced by increased 5-hydroxytryptamine synthesis in rats. J. Neural Transmission 39, 103–112 (1976). https://doi.org/10.1007/BF01248769
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DOI: https://doi.org/10.1007/BF01248769