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PubMed2003

Changes in rectal temperature and ECoG spectral power of sensorimotor cortex elicited in conscious rabbits by i.c.v. injection of GABA, GABA(A) and GABA(B) agonists and antagonists.

1. In order to ascertain whether both GABA(A) and GABA(B), or only GABA(B) receptors, directly modulate thermoregulation in conscious rabbits, GABA(A)/GABA(B) agonist and antagonist agents were injected intracerebroventricularly in conscious rabbits while monitoring changes in rectal temperature (RT), gross motor behaviour (GMB) and electrocorticogram (ECoG) power spectra (ps) from sensorimotor cortices. 2. GABA (48 micromol), nipecotic acid (50 nmol), THIP (60 nmol), muscimol (18 nmol) and baclofen (8 nmol) induced hypothermia (-deltaRTmax values of 1.70+/-0.1, 1.4+/-0.2, 1.0+/-0.4, 1.1+/-0.2 and 1.6+/-0.3 degrees C, respectively), accompanied by inhibition of GMB and ECoG synchronization. THIP increased ps at delta frequency band (1.1-3.3 Hz), while GABA, nipecotic acid, muscimol and baclofen did the same at both delta and (4.6-6.5 Hz) frequency bands. ECoG ps changes were concomitant or even preceded hypothermia. 3. Bicuculline (1.8 nmol) induced hyperthermia (deltaRTmax 1.2+/-0.5 degrees C) and slight excitation of GMB, while CGP35348 (1.2 micromol) did not affect RT nor GMB. Both compounds did not affect ECoG ps. 4. Bicuculline potentiated muscimol-induced hypothermia, inhibition of GMB and synchronization of ECoG, while CGP35348 fully antagonized these effects. 5. In conclusion, the present results, while confirming the prevailing role of GABA(B), also outline a direct involvement of GABA(A) receptors in the central mechanisms of thermoregulation. Ascending inhibition towards discrete cortical areas controlling muscular activity and thermogenesis may result from GABA receptor activation in neurones proximal to the ventricles, thus contributing to hypothermia, although hypothermia-induced reduction of neuronal activity of these cortical areas cannot be ruled out.

Animals↗
PubMed2001

Pretreatment of rat brain synaptosomes with GABA increases subsequent GABA uptake via GABA(B) receptor activation.

Pretreatment with 100 microM GABA of synaptosomes purified from rat brain results in an increased uptake of the labelled neurotransmitter in subsequent incubations. The effect is blocked by a GABA(B) receptor antagonist, 2-hydroxy-saclofen. The effect is mimicked by baclofen and the baclofen effect is blocked by saclofen too. Lower GABA concentrations (up to 50 microM) do not result in an increase of subsequent GABA uptake. Treatment of synaptosomes with 8-Br-cAMP results in a decreased GABA uptake. Since the uptake incubations were run with saturating concentrations of labelled GABA, the data indicates that GABA(B) receptor activation in brain synaptosomes up-regulates their GABA uptake capacity by an increase in Vmax. This mechanism appears of physiological relevance under conditions of sustained GABA release and substantial increase of its extracellular concentration.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1990

The effects of intranigral GABA and dynorphin A injections on striatal dopamine and GABA release: evidence that dopamine provides inhibitory regulation of striatal GABA neurons via D2 receptors.

The effects of injections of gamma-aminobutyric acid (GABA) and dynorphin A into the substantia nigra, pars reticulata on the levels of extracellular dopamine (DA) and GABA in the ipsilateral striatum of halothane-anaesthetized rats were studied using microdialysis. The effects of intranigral injections of substance P and neurokinin A were also studied. Intranigral GABA (300 nmol) or dynorphin A (0.5 nmol) injections produced a simultaneous decrease in DA and increase in GABA levels, while intranigral substance P (0.07 nmol) or neurokinin A (0.09 nmol) injections produced an increase in DA but had no effect on GABA levels. DA agonists, apomorphine (D1/D2), SKF 38393 (D1) and pergolide (D2) were applied locally by perfusing them through the microdialysis probe, each at a concentration of 10(-5) M. All 3 agonists decreased the levels of DA in the striatum. However, while apomorphine and SKF 38393 increased, pergolide decreased the levels of GABA in the striatum. The increase in striatal GABA produced by intranigral injections of GABA (300 nmol) was reversed by local perfusion with pergolide (10(-5) M), but was not reversed by local perfusion with SKF 38393 (10(-5) M). These findings suggest that D1 and D2 receptors differentially regulate striatal GABA release, and are stimulatory and inhibitory, respectively. Furthermore, it is suggested that nigrostriatal DA functions as an inhibitory modulator of striatal GABA neurons, acting via D2 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

GABA-agonists induce the formation of low-affinity GABA-receptors on cultured cerebellar granule cells via preexisting high affinity GABA receptors.

The kinetics of specific GABA-binding to membranes isolated from cerebellar granule cells, cultured for 12 days from dissociated cerebella of 7-day-old rats was studied using [3H]GABA as the ligand. The granule cells were cultured in the presence of the specific GABA receptor agonist 4, 5, 6, 7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol (THIP, 150 microM) or THIP plus the antagonist bicuculline methobromide (150 microM of each) or in the absence of the agonist or antagonist. Membranes isolated from granule cells cultured in a medium without the GABA agonist revealed a single binding site for GABA with a binding constant (KD) of 7.9 +/- 0.4 nM and a Bmax of 3.42 +/- 0.08 pmol X mg-1 protein. Membranes from cells cultured in the presence of THIP had two binding sites for GABA with KD-values of 6.8 +/- 0.9 nM and 476 +/- 311 nM, respectively. The corresponding Bmax values were 4.41 +/- 0.42 pmol X mg-1 and 5.81 +/- 1.20 pmol X mg-1. The effect of culturing the cells in THIP was antagonized by the simultaneous presence of bicuculline in the culture media, i.e. no significant low-affinity binding for GABA was found on the membranes from granule cells cultured in both THIP and bicuculline. The KD value (14.3 +/- 1.4 nM) for the high affinity binding site was, however, slightly increased compared to the non-treated cells. These findings suggest that the ability of THIP to induce formation of low-affinity GABA receptors is mediated by preexisting high-affinity GABA-receptors on the granule cells.

Animals↗
PubMed1983

Use of gamma-aminobutyric acid (GABA)-transaminase inhibitors and a GABA uptake inhibitor to investigate the influence of GABA neurons on dopamine-containing amacrine cells of the rat retina.

The effects of inhibiting gamma-aminobutyric acid-transaminase (GABA-T) with aminooxyacetic acid or with gabaculine and inhibiting GABA uptake with nipecotic acid on dopamine (DA) synthesis in the retina of light-exposed rats were studied. 3,4-Dihydroxyphenylalanine (Dopa) accumulation after the inhibition of L-aromatic amino acid decarboxylase with NSD-1015 was used as an index of DA synthesis. The GABA-T inhibitors significantly increased GABA levels in the retina but had no effect on retinal Dopa accumulation in the light. Dopa accumulation was significantly inhibited at a high dosage by nipecotic acid alone and by low dosages of nipecotic acid in rats pretreated with either aminooxyacetic acid or gabaculine. The dosages of nipecotic acid which inhibited Dopa accumulation in the light also inhibited [3H]GABA uptake in the retina. The inhibitory effects of gabaculine and nipecotic acid on Dopa accumulation appeared to occur at least partially via GABA receptors because their action was significantly reversed by the GABA antagonist bicuculline methiodide. These experiments thus suggest that endogenous GABA can suppress the light-evoked increase in DA synthesis in the rat retina and support previous studies which concluded that an inhibitory GABA input may at least partially regulate the activity of the DA neurons in the retina of rats.

4-Aminobutyrate Transaminase↗
PubMed1991

GABA and pancreatic beta-cells: colocalization of glutamic acid decarboxylase (GAD) and GABA with synaptic-like microvesicles suggests their role in GABA storage and secretion.

GABA, a major inhibitory neurotransmitter of the brain, is also present at high concentration in pancreatic islets. Current evidence suggests that within islets GABA is secreted from beta-cells and regulates the function of mantle cells (alpha- and delta-cells). In the nervous system GABA is stored in, and secreted from, synaptic vesicles. The mechanism of GABA secretion from beta-cells remains to be elucidated. Recently the existence of synaptic-like microvesicles has been demonstrated in some peptide-secreting endocrine cells. The function of these vesicles is so far unknown. The proposed paracrine action of GABA in pancreatic islets makes beta-cells a useful model system to explore the possibility that synaptic-like microvesicles, like synaptic vesicles, are involved in the storage and release of non-peptide neurotransmitters. We report here the presence of synaptic-like microvesicles in beta-cells and in beta-cells. Some beta-cells in culture were found to extend neurite-like processes. When these were present, synaptic-like microvesicles were particularly concentrated in their distal portions. The GABA synthesizing enzyme, glutamic acid decarboxylase (GAD), was found to be localized around synaptic-like microvesicles. This was similar to the localization of GAD around synaptic vesicles in GABA-secreting neurons. GABA immunoreactivity was found to be concentrated in regions of beta-cells which were enriched in synaptic-like microvesicles. These findings suggest that in beta-cells synaptic-like microvesicles are storage organelles for GABA and support the hypothesis that storage of non-peptide signal molecules destined for secretion might be a general feature of synaptic-like microvesicles of endocrine cells.

Animals↗
PubMed2004

Independent maturation of the GABA(B) receptor subunits GABA(B1) and GABA(B2) during postnatal development in rodent brain.

GABA(B) receptors mediate slow inhibitory GABAergic neurotransmission. They are encoded by two distinct subunits, GABA(B1) (GBR1) and GABA(B2) (GBR2), with two major isoforms of GBR1, GBR1a and GBR1b, arising from differential promoter usage. Heterodimerization of GBR1 and GBR2 is essential for GABA(B) receptor function, as shown in recombinant expression systems and in GBR1(-/-) mice. GABA(B) receptors are highly expressed during ontogeny, prior to synaptogenesis, but their developmental function remains elusive. Here we investigated the postnatal development of GABA(B) receptors in rodent brain, focusing on potential differences in the spatial and temporal expression pattern of GBR1 and GBR2. Immunohistochemistry with subunit-specific antibodies revealed a widespread staining for GBR1a and GBR2 in neonatal rodent brain. During the first 2 weeks, these two subunits exhibited largely overlapping regional distribution, but with profound distinctions in cellular and subcellular localization. The adult-like pattern was established during the third week, with a prominent up-regulation of GBR1b, extensively codistributed with GBR2. Several unexpected features were noted at early stages, notably, a selective GBR2 staining of axonal tracts, such as the corticothalamic projection, and a prominent GBR1 expression in astrocytes. The specificity of the antibody labeling was verified in GBR1- and GBR2-knockout mice. In addition, the analysis of these mutants revealed a partial preservation of GBR2 staining in GBR1(-/-) mice and vice versa. Altogether, the results suggest a functional role for GBR1 and GBR2 proteins in immature brain in addition to their contribution to dimeric GABA(B) receptor complexes.

Amino Acid Transport Systems↗
PubMed1986

Stereoselective uptake of the GABA-transaminase inhibitors gamma-vinyl GABA and gamma-acetylenic GABA into neurons and astrocytes.

The cellular uptake of the GABA-transaminase inhibitors gamma-vinyl GABA (GVG) and gamma-acetylenic GABA (GAG) was studied in cultured neurons and astrocytes. By the use of the individual enantiomers R- and S-GVG and R- and S-GAG it could be shown that in both cell types only the S-enantiomers could be actively transported. Comparing neurons and astrocytes only neurons exhibited a high affinity uptake system for S-GVG (Km 78.2 +/- 20.3 microM; Vmax 0.71 +/- 0.06 nmol.min-1.mg-1 cell protein). In case of S-GAG it could not be established with certainty whether the neuronal uptake was of the high affinity type. Both GVG and GAG were studied as inhibitors of GABA uptake into neurons and astrocytes. S-GVG and S-GAG were found to be weak inhibitors of GABA uptake suggesting that S-GVG is not transported by the GABA carrier in neurons. The finding of a much more efficient uptake of S-GVG into neurons than into astrocytes is in line with the previous observation that neuronal GABA-T is more sensitive than astrocytic GABA-T to S-GVG.

4-Aminobutyrate Transaminase↗
PubMed1995

The effect of chronic treatment with the GABA transaminase inhibitors gamma-vinyl-GABA and ethanolamine-O-sulphate on the in vivo release of GABA from rat hippocampus.

The effects of chronic treatment with the specific, mechanism-based, irreversible inhibitors of 4-aminobutyrate aminotransferase (EC 2.6.1.19; GABA transaminase), ethanolamine O-sulphate (EOS), and 4-aminohexenoate [vigabatrin; gamma-vinyl-GABA (GVG)] on the extracellular concentrations of GABA in the hippocampus have been studied using in vivo microdialysis in conscious animals. Oral dosing [3 mg/ml of drinking water, giving doses of GVG of 194 +/- 38 mg/kg/day and of EOS of 303 +/- 42 mg/kg/day (mean +/- SD)] was followed by microdialysis at 2, 8, and 21 days. The basal outflow of GABA (in the range of approximately 1-2 pmol/30 microliters/30-min sample) after 2 and 8 days of treatment was not significantly different from that in control animals, but the 21-day treatment gave significant rises in the extracellular GABA concentration (up to approximately 6-8 pmol/30 microliters/30-min sample). Both inhibitors gave similar results. Depolarisation with 100 mM K+ gave large increases in GABA release in control (approximately 20-60 pmol/30 microliters/30-min sample) and treated animals. The 8- and 21-day-treated animals showed significant increases in the stimulated release compared with control animals (approximately 80-100 pmol/30 microliters/30-min sample). Excluding Ca2+ had no significant effect on either basal or stimulated release. The significant increases in K(+)-evoked release of GABA show that the increased intracellular pool of GABA is available for release, and this may be related to the anticonvulsant action of these compounds.

4-Aminobutyrate Transaminase↗
PubMed1999

Measurement of GABAergic parameters in the prefrontal cortex in schizophrenia: focus on GABA content, GABA(A) receptor alpha-1 subunit messenger RNA and human GABA transporter-1 (HGAT-1) messenger RNA expression.

The hypothesis that the pathophysiology of schizophrenia may be associated with a dysfunction in GABA transmission in the human prefrontal cortex was investigated. Human post mortem brain tissue from 10 control cases and six cases of schizophrenia were processed for amino acid analysis and for radioactive in situ hybridization. Laminae III and V of three prefrontal cortical areas were examined in detail, namely Brodmann areas 9, 10 and 11. Of these three areas significant changes in GABAergic markers were found only in areas 9 and 10. Of note, a significant decrease in the tissue content of GABA was observed and this was accompanied by a marked increase in the cellular expression of the GABA(A) receptor alpha-1 subunit messenger RNA and a marked decrease in the expression of human GABA transporter-1, the messenger RNA encoding the neuronal GABA transporter protein. The amino acid analysis data provided in this study coupled with the detailed cellular study of several GABAergic markers in the human prefrontal cortex provide direct evidence in support of a disturbance in GABA transmission in the prefrontal cortex, which may be loosely termed "hypofrontality".

Aged↗
PubMed1985

GABA-noradrenergic interaction: evidence for differential sites of action for GABA-A and GABA-B receptors.

Treatment of mice with DSP4 (a neurotoxin that abolishes the presynaptic noradrenergic neuron; Dooley et al., 1983) resulted in: (A) a decrease in the Bmax for the low affinity GABA-B receptor site in the cerebral cortex and hippocampus, whereas the Bmax for the high affinity GABA-B receptor site was unaffected; (B) a greater potentiation of norepinephrine stimulated adenylate cyclase by baclofen in cerebral cortex slices; and (C) a decrease in the Bmax for both the high and low affinity GABA-A receptor sites in the cerebral cortex and hippocampus. These data, coupled with previous work from our laboratory, suggest that the GABA-B receptor may be associated with both the noradrenergic nerve terminal and the post-synaptic neuron receiving noradrenergic input, whereas the GABA-A receptor may be associated with the noradrenergic nerve terminal. These data further suggest a functional coupling between the noradrenergic and GABA-ergic systems.

Adrenergic Fibers↗
PubMed1990

Synthesis, brain uptake, and pharmacological properties of a glyceryl lipid containing GABA and the GABA-T inhibitor gamma-vinyl-GABA.

1-O-Linolenoyl-2-O-(4-aminobutyryl)-3-O-(4-vinyl-4-aminobutyryl)glycerol (LGV) was synthesized as an example of a prodrug which readily penetrates the blood-brain barrier (brain penetration index 97% +/- 15%) and releases two active substances in the central nervous system (CNS): GABA (4-aminobutanoic acid) and the GABA transaminase inhibitor (GABA-T) of GABA breakdown. In vitro studies showed that the compound can inhibit GABA-T after hydrolysis by CNS esterases and that it enhanced GABAergic inhibition when applied to rat hippocampus slices. In vivo studies indicate that LGV depresses the spontaneous locomotor activity of mice. Its activity on a molar basis was some 300 times greater than that of gamma-vinyl-GABA.

4-Aminobutyrate Transaminase↗
PubMed1998

GABA, GABA transporters, GABA(A) receptor subunits, and GAD mRNAs in the rat parabrachial and Kölliker-Fuse nuclei.

In the present study, we investigated the key molecules that determine gamma-aminobutyric acid (GABA)ergic signal transduction in the parabrachial/Kölliker-Fuse complex (PB/KF) by means of immunocytochemistry and in situ hybridization. Our data demonstrate a dense plexus of GABA-immunoreactive (-ir) varicosities throughout the nuclei of the PB and the KF. The number of neurons expressing GAD65 or GAD67 mRNA was fairly low in the PB, whereas caudally in the KF an accumulation of GAD-expressing neurons was observed. The GABA transporter-3 (GAT-3) was detected in all parts of the PB/KF, whereas immunolabeling for GAT1 was not observed. All nuclei of the PB and the KF exhibited immunoreactivity for the gamma2-, alpha2-, and alpha3-subunits of the GABA(A) receptor. Gamma2-ir was strong and similar in all PB/KF nuclei. In contrast, alpha2-labeling was particularly intense in the superior lateral PB, and alpha3-labeling was most prominent in the external lateral and external medial PB, compared with the remaining nuclei. With respect to the subcellular localization, we found gamma2-ir in cell bodies and higher order dendrites, whereas alpha2- and alpha3-ir was predominantly found in cell bodies. Immunolabeling for the beta2/3- and the alpha1-subunit was seen in cell bodies and presumed dendritic profiles. The staining intensity was strongest in the dorsal lateral PB. Most importantly, the external lateral PB and the waist area were totally devoid of beta2/3- and alpha1-ir. Our data suggest that neural processing in the PB/KF is under a strong GABAergic inhibition that is apparently mediated by different types of GABA(A) receptors in functionally different pathways through the PB/KF.

Animals↗
PubMed1981

Treatment of Huntington disease with gamma-acetylenic GABA an irreversible inhibitor of GABA-transaminase: increased CSF GABA and homocarnosine without clinical amelioration.

gamma-Acetylenic GABA (GAG, RMI 71.645), a potent irreversible inhibitor of gamma-aminobutyric acid transaminase, was given orally in various dosage schedules to 14 patients with Huntington disease. The biochemical effects of the drug on cerebrospinal fluid (CSF) concentrations of gamma-aminobutyric acid (GABA) and the GABA-containing dipeptide, homocarnosine, were measured in 10 of 14 patients. Treatment with GAG increased CSF concentrations of GABA and homocarnosine as compared to pretreatment values, suggesting that the drug increased brain GABA concentration. Despite this neurochemical effect, the clinical state was not improved. Except for single seizure episodes in five patients, GAG therapy was well tolerated. These results do not exclude the possibility that agents that augment CNS GABAergic function may prove useful in therapy of Huntington disease.

4-Aminobutyrate Transaminase↗
PubMed1978

Blockade of epileptic responses in the photosensitive baboon, Papio papio, by two irreversible inhibitors of GABA-transaminase, gamma-acetylenic GABA (4-amino-hex-5-ynoic acid) and gamma-vinyl GABA (4-amino-hex-5-enoic acid).

The anticonvulsant potency and neurological toxicity of two new catalytic inhibitors of GABA-transaminase have been assessed in acute experiments in baboons with a natural syndrome of photic epilepsy. gamma-Acetylenic GABA, 160--200 mg/kg, or gamma-vinyl GABA, 450--950 mg/kg, intravenously, gave complete protection against generalised myoclonus or seizure responses induced by photic stimulation (in baboons without or with priming with subconvulsant doses of allylglycine). The protection became maximal 1--3 h after injection, and continued for 7--24 h. Signs characteristic of the acute toxicity of anticonvulsant drugs (nystagmus and ataxia) were not seen. The potential use of these compounds in human epilepsy deserves investigation.

4-Aminobutyrate Transaminase↗
PubMed1988

Levels of total gamma-aminobutyric acid (GABA), free GABA and homocarnosine in cerebrospinal fluid of epileptic patients before and during gamma-vinyl-GABA (vigabatrin) treatment.

Levels of total gamma-aminobutyric acid (TGABA), free GABA (FGABA), and homocarnosine (HC) were studied in CSF taken from 12 controls and 28 patients with drug-refractory epilepsy before and during 7 months of gamma-vinyl-GABA (GVG) administration. At baseline TGABA and FGABA in CSF of epileptic patients did not differ from that of the controls. In epileptic patients HC was 127% of that in controls. During GVG treatment TGABA was 283%, FGABA 197%, and HC 310% of the levels at baseline in the same patients. The patients who had over 50% reduction in seizure frequency during GVG (responders, 46% of the study population) at baseline had higher TGABA and HC in CSF than patients with less than 50% reduction in seizures (non-responders). During GVG the responders and nonresponders had similar levels of different GABAergic markers. The present study shows that in man GVG treatment effectively suppresses seizures in nearly half of the epileptic patients who had previously been drug-refractory. The elevated levels of GABAergic markers in CSF are not, however, necessarily related to good seizure control during GVG.

Adolescent↗
PubMed2003

Effects of GABA agonists on body temperature regulation in GABA(B(1))-/- mice.

1. Activation of GABA(B) receptors evokes hypothermia in wildtype (GABA(B(1))+/+) but not in GABA(B) receptor knockout (GABA(B(1))-/-) mice. The aim of the present study was to determine the hypothermic and behavioural effects of the putative GABA(B) receptor agonist gamma-hydroxybutyrate (GHB), and of the GABA(A) receptor agonist muscimol. In addition, basal body temperature was determined in GABA(B(1))+/+, GABA(B(1))+/- and GABA(B(1))-/- mice. 2. GABA(B(1))-/- mice were generated by homologous recombination in embryonic stem cells. Correct gene targeting was assessed by Southern blotting, PCR and Western blotting. GABA(B) receptor-binding sites were quantified with radioligand binding. Measurement of body temperature was done using subcutaneous temperature-sensitive chips, and behavioural changes after drug administration were scored according to a semiquantitative scale. 3. GABA(B(1))-/- mice had a short lifespan, probably caused by generalised seizure activity. No histopathological or blood chemistry changes were seen, but the expression of GABA(B(2)) receptor protein was below the detection limit in brains from GABA(B(1))-/- mice, in the absence of changes in mRNA levels. 4. GABA(B) receptor-binding sites were absent in brain membranes from GABA(B(1))-/- mice. 5. GABA(B(1))-/- mice were hypothermic by approximately 1 degrees C compared to GABA(B(1))+/+ and GABA(B(1))+/- mice. 6. Injection of baclofen (9.6 mg kg-1) produced a large reduction in body temperature and behavioural effects in GABA(B(1))+/+ and in GABA(B(1))+/- mice, but GABA(B(1))-/- mice were unaffected. The same pattern was seen after administration of GHB (400 mg kg-1). The GABA(A) receptor agonist muscimol (2 mg kg-1), on the other hand, produced a more pronounced hypothermia in GABA(B(1))-/-mice. In GABA(B(1))+/+ and GABA(B(1))+/- mice, muscimol induced sedation and reduced locomotor activity. However, when given to GABA(B(1))-/- mice, muscimol triggered periods of intense jumping and wild running. 7. It is concluded that hypothermia should be added to the characteristics of the GABAB(1)-/-phenotype. Using this model, GHB was shown to be a selective GABAB receptor agonist. In addition, GABAB(1)-/- mice are hypersensitive to GABAA receptor stimulation, indicating that GABAB tone normally balances GABAA-mediated effects.

Animals↗