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PubMedDate not supplied

Levels of free gamma-aminobutyric acid and other neuroactive amino acids in cerebrospinal fluid of patients with neurological disorders.

Concentrations of free gamma-aminobutyric acid, other neuroactive amino acids and related compounds were determined in CSF of 42 patients with ischemic stroke, 8 patients with vascular encephalopathy and 14 patients with neurological syndromes of spine degenerative disorders. CSF levels of amino acids were obtained by isocratic HPLC with electrochemical detection after precolumn derivatization. The results obtained indicate that the correlations between assay compounds alter, absolute amounts of their content being unchanged.

Adult↗
PubMed1983

Endogenous gamma-hydroxybutyrate in rat brain areas: postmortem changes and effects of drugs interfering with gamma-aminobutyric acid metabolism.

The possibility that gamma-hydroxybutyrate (GHB), a metabolite of gamma-aminobutyric acid (GABA), may play a role in the CNS has recently come to attention. We describe here a sensitive and specific mass fragmentographic technique that allows the measurement of picomole amounts of GHB in single rat brain areas. Moreover, we show that GHB can accumulate postmortem, an effect that is blocked by the use of microwave irradiation to kill the animals. To understand further the relationship between GABA and GHB formation, we treated rats with drugs known to interfere with GABA metabolism at different levels and concomitantly measured GABA and GHB in cerebral cortex and cerebellum. Isoniazide, which blocks the formation of GABA, also decreases GHB. Blockers of the catabolism of GABA, such as aminooxyacetic acid and gamma-acetylenic GABA, increase GABA levels and decrease those of GHB. Sodium dipropylacetate increases both GABA and GHB, supporting the hypothesis that this effective antiepileptic drug also blocks in vivo the enzyme that converts succinic semialdehyde to succinic acid.

Alkynes↗
PubMed1990

Effects of anticonvulsants and gamma-aminobutyric acid (GABA)-mimetic drugs on immunoreactive somatostatin and GABA contents in the rat brain.

Immunoreactive somatostatin (IR-SRIF) and gamma-aminobutyric acid (GABA) contents in the rat brain were investigated to study chronic effects of the treatment with anticonvulsants, carbamazepine (CBZ), valproic acid (VPA) and phenytoin (PHT). Decreased IR-SRIF levels were found in several brain regions after chronic treatment with VPA and CBZ. GABA concentrations were found to be increased significantly in chronic CBZ and VPA treatment in the rat brain, especially in limbic structures. PHT had no effect on both IR-SRIF and GABA contents in the rat brain. Effects of several GABA-mimetic drugs also were studied on IR-SRIF contents in the rat brain. Aminooxyacetic acid an inhibitor of GABA transaminase, induced a decrease in IR-SRIF concentration in the pyriform and entorhinal cortex, whereas ethanolamine-o-sulfate, another GABA-transaminase inhibitor and muscimol, a GABA receptor agonist had no effect on brain IR-SRIF after acute administration. The present results suggest that endogenous somatostatin has an important role for anticonvulsant properties of CBZ and VPA, but not of PHT. The relationship between the changes in IR-SRIF and the GABA transmitter system in the anticonvulsant action of CBZ and VPA remains to be clarified.

Aminooxyacetic Acid↗
PubMed1986

Effect of clonidine and gamma-aminobutyric acid on the discharges of medullo-spinal sympathoexcitatory neurons in the rat.

Single-unit recordings of 50 pressure-sensitive neurons with axonal projections to the thoracic spinal cord were obtained in the retrofacial portion of nucleus paragigantocellularis lateralis of halothane-anesthetized rats. Two types of cells were distinguished on the basis of their axonal conduction velocities: a slow-conducting (mean 0.6 m/s, group I) and a fast-conducting one (group II, mean 3.3 m/s). Both cell types were completely silenced by elevating mean arterial pressure above 160 mm Hg by means of aortic constriction and exhibited a plateau of high spontaneous activity below 70 mm Hg. Only group I neurons were significantly inhibited by the administration of clonidine in a dose producing 90% of its maximum hypotensive effect (11.5 micrograms/kg, i.v.). Hypotensive doses of clonidine administered into the fourth ventricle also produced a selective inhibition of group I neurons, while the others were unaffected. Iontophoretic applications of clonidine and norepinephrine produced an inhibition of the discharges of group I neurons qualitatively and quantitatively identical to that observed following administration of clonidine by the i.v. or i.c.v. route. Once more, group II cells were unaffected. In contrast, iontophoretically applied gamma-aminobutyric acid exerted a powerful inhibition of both cell types, an effect which was totally prevented or reversed by the gamma-aminobutyric acid antagonist bicuculline. Anatomical experiments were performed to uncover the potential source of catecholaminergic innervation of the area in which recordings were obtained. This area contains a large number of adrenaline-synthesizing neurons and receives a selective noradrenergic input from the A5 pontine group with no contribution from the A1, A2, A6 and A7 brainstem clusters of noradrenergic cells.

Animals↗
PubMed1988

Differential modulation of striatal dopamine release by intranigral injection of gamma-aminobutyric acid (GABA), dynorphin A and substance P.

The effects of intranigral injection of gamma-aminobutyric acid (GABA) (dose range: 10.0-300.0 nmol), dynorphin A (0.005-0.5 nmol) and substance P (0.00007-7.0 nmol) on striatal dopamine (DA) release, and dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) formation were studied by microdialysis. It was found that both GABA and dynorphin A produced a dose-dependent decrease in the release of striatal DA following injection into the ipsilateral substantia nigra, the pars reticulata. In contrast, intranigral injection of substance P produced an increase in DA release. However, the dose-response curve for the substance P effect had a biphasic shape. The maximum effect was produced by 0.007 nmol, whereas higher doses (0.07-0.7 nmol) produced less pronounced effects. At the highest dose (7.0 nmol), substance P produced a strong decrease of DA release. Striatal levels of DOPAC and HVA were enhanced by GABA, dynorphin A and substance P. The present results support the concept that substance P, directly or indirectly, provides a positive feed-back regulation for the release of striatal DA, whereas GABA and dynorphin exert a negative feed-back regulation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

Metabolism of polyamines by cultured glioma cells. Effect of asparagine on gamma-aminobutyric acid concentrations.

The activity of ornithine decarboxylase (EC 4.1.1.17) increased in confluent cultures of glioma C6BU-1 cells 3 h after adding a complete serum-containing medium, and was maximal 5 h later. The activity of S-adenoxyl-L-methionine decarboxylase (EC 4.1.1.50) increased soon after addition of the complete medium to the cells, and reached its peak after 11 h. The activity of diamine oxidase (EC 1.4.3.6) also increased soon after adding complete medium and was maximal 8h later, when the activity of ornithine decarboxylase reached its peak. The increase in the activity of S-adenosyl-L-methionine decarboxylase was accompanied by changes in cellular spermidine and spermine concentrations, whereas the increase in the activity of diamine oxidase was followed by the accumulation of gamma-aminobutyric acid, which was detected both in the cells and in the medium. Asparagine enhanced the utilization of radioactive putrescine by glioma cells suspended in buffered-salt/glucose solution and increased intracellular and extracellular gamma-aminobutyric acid concentrations. Radioactive putrescine was converted into spermidine and spermine by glioma cells after addition of a serum-containing medium, but not after adding buffered--salt/glucose solutions, in the presence or absence of asparagine. The kinetics of ornithine decarboxylase 'induction' and the half-life of the enzyme differed in cells incubated with buffered asparagine solutions and serum-containing media.

Amine Oxidase (Copper-Containing)↗
PubMedDate not supplied

[The role of gamma-aminobutyric acid in the mechanism of action of anticonvulsant drugs].

Decreased activity of gamma-aminobutyric acid, the major inhibitory neurotransmitter in CNS can be epileptogenic. Manipulation of the GABA system has been a target for development of antiepileptic drugs. The different ways for augmenting gabaergic inhibition by conventional and new AEDs are presented in this paper. Among the I generation, barbiturates and benzodiazepines are potent anticonvulsants that act as GABA modulators in postsynaptic GABA-A receptor complex but their usefulness is limited by dependence and tolerance to antiseizure activity. The II generation drugs vigabatrin and tiagabine, and to some extent gabapentin have been developed by a rationale strategy and none of them exert direct action in GABA receptors. Only two former drugs exhibit selective, strictly defined activity: vigabatrine is an irreversible inhibitor of GABA-aminotransferase and tiagabine acts as a GABA-uptake inhibitor from synaptic cleft into neurons and glia. Gabapentin binds to a novel receptors in epileptogenic areas in CNS and enhances GABA turnover. Drugs with multiple mechanisms of action, felbamate and topiramate not only potentiate gabaergic inhibition in several ways but also diminish the activity of excitatory amino acids at their NMDA or AMPA receptors; the later mechanism seems to be essential for their potential neuroprotective activity in epileptogenesis. None of gabamimetic drugs provide optimal seizure control but better tolerability of newer ones and well-established mechanisms of action provide possible harmless therapy.

4-Aminobutyrate Transaminase↗
PubMed1991

Autoradiographic changes in central benzodiazepine binding sites and their coupling to gamma-aminobutyric acid receptors after seizures in the developing rat.

Benzodiazepines are psychoactive substances classically used for their anticonvulsant properties in neonates as well as in adults. In a previous work, we have shown that seizures lead to an age-dependent upregulation of central benzodiazepine binding sites measured in isolated rat cerebral membranes. However, information concerning regional changes in the receptor density was lacking. In our present study, the effects of bicuculline-induced seizures were investigated by quantitative autoradiography of central benzodiazepine receptors in developing rats and in adults. Animals were killed 30 min after an intraperitoneal injection of either saline or a convulsive dose of bicuculline. Benzodiazepine binding sites in brain sections were labeled by [3H]flunitrazepam. Generalized seizures induced a widespread increase in benzodiazepine receptors, with a marked enhancement in structures that mediate seizure activity, such as substantia nigra, amygdala, septum, and hippocampus. The addition of exogenous gamma-aminobutyric acid to the incubation medium increased benzodiazepine binding by the same order of magnitude whether rats were given saline or bicuculline, suggesting that additional benzodiazepine sites are also functionally linked to gamma-aminobutyric acid receptors. The age-related postictal increase in benzodiazepine receptors might reflect a compensatory response for protection against recurrent seizures, especially in newborns.

Age Factors↗
PubMed1979

Structure-activity studies on the inhibition of gamma-aminobutyric acid uptake in brain slices by compounds related to nipecotic acid.

Various N-methyl derivatives of nipecotic acid and related compounds were tested as inhibitors of gamma-aminobutyric acid (GABA) uptake into mini slices. N-Methylnipecotic acid, N,N-dimethylnipecotic acid, N-methylguvacine, and N-methylnicotinic acid were effective inhibitors. None of them, however, were as potent as nipecotic acid itself. All the effective inhibitors, including nipecotic acid, also inhibited the uptake of L-proline, but to a much lesser extent. Four of the test compounds produced a depressant action on cerebral cortical neurons, but even N-methylisoguvacine, the most potent in this respect, was considerably less active than GABA. None of the test compounds caused any clearly discernible changes in the gross behaviour or appearance of mice in the 1-h period following intramuscular injection. It was concluded that methylation of the N atom of nipecotic acid and its derivatives was unlikely to lead to the development of agents with greater experimental or therapeutic potential than that of nipecotic acid itself, if the action of the agent was dependent on its effects on GABA uptake.

Action Potentials↗
PubMed1988

The action of gamma-aminobutyric acid on the horizontal cells of the skate retina.

The effects of gamma-aminobutyric acid (GABA) were studied in the superfused retina of the skate. Intracellular recordings were made from horizontal cells. After application of 500 microM GABA there was a depolarization of the membrane potential, a decrease in the light-evoked amplitude of the response and an increase in the duration of the waveform.

Animals↗
PubMed1991

Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed in the retina.

Type A gamma-aminobutyric acid (GABAA) receptors are a family of ligand-gated chloride channels that are the major inhibitory neurotransmitter receptors in the nervous system. Molecular cloning has revealed diversity in the subunits that compose this heterooligomeric receptor, but each previously elucidated subunit displays amino acid similarity in conserved structural elements. We have used these highly conserved regions to identify additional members of this family by using the polymerase chain reaction (PCR). One PCR product was used to isolate a full-length cDNA from a human retina cDNA library. The mature protein predicted from this cDNA sequence in 458 amino acids long and displays between 30 and 38% amino acid similarity to the previously identified GABAA subunits. This gene is expressed primarily in the retina but transcripts are also detected in the brain, lung, and thymus. Injection of Xenopus oocytes with RNA transcribed in vitro produces a GABA-responsive chloride conductance and expression of the cDNA in COS cells yields GABA-displaceable muscimol binding. These features are consistent with our identification of a GABA subunit, GABA rho 1, with prominent retinal expression that increases the diversity and tissue specificity of this ligand-gated ion-channel receptor family.

Amino Acid Sequence↗
PubMed1979

Running fits and gamma-aminobutyric acid of the superior colliculus of the mouse.

The present experiment was performed to examine the relationship between the content of gamma-aminobutyric acid of the superior colliculus and running fits induced by injection of semicarbazide (SC), an antivitamin B6, into the superior colliculus of the mouse. (1) The distribution of 4-aminobutyrate: 2-oxoglutarate aminotransferase [EC 2.6.1.19] of the superior colliculus was studied histochemically. A high activity was observed in the superficial and medial gray layers of the superior colliculus. Pretreatment with aminooxyacetic acid at a dose which inhibits running fits induced by intracollicular injection of SC depressed the activity. (2) The contents of gamma-aminobutyric acid in superior colliculi of mice which received an intracollicular injection of SC were 60 per cent of the control, when measured immediately after the first running fit. Administration of pyridoxine together with SC inhibited the fall. (3) Intracollicular injection of thiosemicarbazide and 4-deoxypyridoxine, other antivitamins B6, also induced running fits. These results suggest that the running fits by SC injected intracollicularly are induced by the decrease of gamma-aminobutyrate due to insufficient vitamin B6 in the superior colliculus.

Aminooxyacetic Acid↗
PubMed2000

Neuropeptide Y Y5 receptor protein in the cortical/limbic system and brainstem of the rat: expression on gamma-aminobutyric acid and corticotropin-releasing hormone neurons.

Neuropeptide Y displays diverse modes of action in the CNS including the modulation of cortical/limbic function. Some of these physiological actions have been at least partially attributed to actions of neuropeptide Y on the Y5 receptor subtype. We utilized an antibody raised against the Y5 receptor to characterize the distribution of this receptor subtype in the rat cortical/limbic system and brainstem. Y5-like immunoreactivity was located primarily in neuronal cell bodies and proximal dendritic processes throughout the brain. In the cortex, Y5 immunoreactivity was limited to a subpopulation of small gamma-aminobutyric-acid interneurons (approximately 15 microm diameter) scattered throughout all cortical levels. Double label immunofluorescence was also used to demonstrate that all of the Y5 immunoreactive neurons in the cortex displayed intense corticotropin releasing hormone immunoreactivity. The most intense Y5 immunoreactive staining in the hippocampus was located in the pyramidal cell layer of the small CA2 subregion and the fasciola cinerea, with lower levels of staining in the hilar region of the dentate gyrus and CA3 subregion of the pyramidal cell layer. Nearly all of the Y5 immunoreactive neurons in the hilar region of the hippocampus displayed gamma-aminobutyric-acid immunoreactivity. In the brainstem, Y5 immunoreactivity was most intense in the Edinger-Westphal nucleus, locus coeruleus and the mesencephalic trigeminal nucleus. The present study provides neuroanatomical evidence for the possible sites of action of the neuropeptide Y/Y5 receptor system in the control of cortical/limbic function. The presence of Y5 immunoreactivity on cell bodies and proximal dendritic processes in specific regions of the hippocampus suggests that this receptor functions to modulate postsynaptic activity. These data also suggest that the neuropeptide Y/Y5 system may play a role in the modulation of a specific population of GABAergic neurons in the cortex, namely those that contain corticotropin-releasing hormone. The location of the Y5 receptor immunoreactivity fits with the known physiological actions of neuropeptide Y and this receptor.

Animals↗
PubMed1988

Central inhibition by gamma-aminobutyric acid of the release of vasopressin by carbachol in the rat.

1. gamma-Aminobutyric acid (GABA) inhibited the antidiuretic response and the increased urinary excretion of vasopressin produced by carbachol when both drugs were injected into a lateral cerebral ventricle (i.c.v.) in the water-loaded rat under ethanol anaesthesia. 2. The inhibitory effect of GABA was mimicked by muscimol and 3-amino-1-propane sulphonic acid (3-APS) and blocked by bicuculline. 3. GABA injected i.v. or into the cisterna magna (i.cist.) did not inhibit the release of vasopressin by carbachol injected i.c.v. 4. The results suggest a role for GABA as a putative inhibitory transmitter in the hypothalamo-neurohypophysial system, acting directly on the supraoptic or paraventricular nuclei in the anterior hypothalamus.

Animals↗