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PubMedDate not supplied

Comparative study of the anticonvulsant effect of gamma-aminobutyric acid agonists in the feline kindling model of epilepsy.

We made a comparative study of the anticonvulsant effect of GABA agonists on feline amygdala or hippocampal kindled seizures. Progabide (PGB) [gamma-aminobutyric acid (GABA) receptor agonist 25-100 mg/kg intraperitoneally, i.p.] significantly reduced both the kindled seizure stage and after discharge (AD) duration in a dose-dependent manner. SKF89976A (GABA uptake inhibitor 0.5-2.0 mg/kg i.p.) also significantly reduced the kindled seizure stage. Toxic doses of SKF89976A caused generalized paroxysmal EEG discharges and myoclonus, but AD generation in the kindled focus was suppressed completely. Furthermore, gamma-vinyl GABA (GABA catabolic enzyme inhibitor, GVG 50-200 mg/kg i.p.) significantly reduced the seizure stage, while causing prolongation of the AD duration. In contrast, baclofen (selective GABAB receptor agonist, 1 or 5 mg/kg) did not show anticonvulsant effects on any parameters of kindled seizures. Therefore, these GABA agonists, which potentiate the inhibitory function of the GABAA systems, have potent anticonvulsant effects on partial onset and secondarily generalized limbic seizures.

Aminocaproates↗
PubMed1990

Stimulation of luteinizing hormone release by gamma-aminobutyric acid (GABA) agonists: mediation by GABAA-type receptors and activation of chloride and voltage-sensitive calcium channels.

The mechanism by which gamma-aminobutyric acid (GABA) stimulates the release of LH was analyzed in cultured female rat pituitary cells. In 3-h incubations, GABA (1-100 microM) caused a dose-dependent increase in LH release, with the maximal response about 16% of that evoked by 10 nM GnRH. GABA action was independent of the GnRH receptor, since 1 microM GnRH antagonist [( N-acetyl-D-p-Cl-Phe1,2,D-Trp3,D-Lys6,D-Ala10] GnRH), which completely inhibits GnRH action, did not affect the response to GABA. In studies on the effects of GABA receptor agonists and antagonists, 4,5,6,7-tetrahydoisoxazolo-[5,4-c]pyridin-3(2H)-one (THIP) and muscimol (GABAA agonists) gave similar response patterns, with the same maximal stimulation as GABA but much higher potencies. In contrast, the GABAB receptor agonist baclofen did not stimulate LH release. The GABAA receptor antagonist SR95531 caused dose-dependent inhibition of the LH-releasing effects of GABA and muscimol (10 microM), with complete blockade at 10 microM SR95531. T-Butylbicyclophosphorothionate, an inhibitor of the GABAA receptor-associated chloride channel, also dose-dependently reduced the releasing effect of 100 microM GABA. These results indicate that GABA action is mediated by the chloride channel-associated GABAA receptor. However, the other GABAA receptor antagonists, including bicuculline, picrotoxin, and strychnine, did not attenuate the LH-releasing effect of 100 microM GABA in concentrations up to 100 microM, suggesting that GABA action is mediated by nonclassical GABAA receptors. Incubation in the presence of nifedipine (1 microM) or in calcium-free medium inhibited the LH-releasing action of GABA, indicating that calcium influx through voltage-sensitive calcium channels (VSCC) is required for GABA-induced LH release. Such entry of Ca2+ would result from activation of VSCC by depolarization due to the increased Cl- conductance caused by GABAA receptor activation. In cell perfusion studies, the actions of GABA and muscimol were attenuated or abolished after repetitive stimulation, consistent with desensitization of the GABA receptors. These findings have demonstrated that the stimulation of LH release by GABA is independent of GnRH action, occurs via binding to nonclassical GABAA receptors, which rapidly desensitize, and is mediated by the activation of VSCC.

Amino Acid Sequence↗
PubMed2000

Serotonin potentiates the response of neurons of the superficial laminae of the rat spinal dorsal horn to gamma-aminobutyric acid.

Employing the Nystatin-perforated whole-cell patch-clamp recording technique, the modulatory effects of serotonin (5-HT) on gamma-aminobutyric acid (GABA)-activated whole-cell currents were investigated in neurons acutely dissociated from the superficial laminae (laminae I and II) of the rat spinal dorsal horn. The results showed: (1) GABA acted on GABA(A) receptors and elicited inward Cl(-) currents (I(GABA)) at a holding potential (V(H)) of -40 mV; (2) 5-HT potentiated GABA-induced Cl(-) current without affecting the reversal potential of I(GABA) and the apparent affinity of GABA to its receptor; (3) alpha-methyl-5-HT, a selective agonist of 5-HT(2) receptor, mimicked the potentiation effect of 5-HT on I(GABA), whereas ketanserine, an antagonist of 5-HT(2) receptor, blocked the potentiation effect of 5-HT; (4) Chelerythrine, an inhibitor of protein kinase C, reduced the potentiation effect of 5-HT on I(GABA). The present results indicate: (1) The potentiation of 5-HT on I(GABA) is mediated by 5-HT(2) receptor and through a protein kinase-dependent transduction pathway; (2) The interactions between 5-HT and GABA might play an important role in the modulation of nociceptive information transmission at spinal cord level.

Animals↗
PubMed1977

Effect of convulsant and anticonvulsant agents on level and metabolism of gamma-aminobutyric acid in mouse brain.

1. The effect of the convulsant agents pentetrazole, picrotoxin, bicuculline, strychnine and isoniazid on the central level of gamma-aminobutyric acid (GABA) and the activity of the enzymes glutamate decarboxylase (GAD) and GABA-alpha-oxoglutarate aminotransferase (GABA-T) from mice brain was studied in vivo and vitro. In vivo, convulsant doses of picrotoxin and isoniazid lowered the level of GABA and the activity of GAD, whereas strychnine and bicuculline had no such effect. Pentetrazole inhibited GAD, but did not alter the GABA content. In vitro, all convulsants, except bicuculline, inhibited the activity of GAD; however, the concentrations of strychnine were far beyond the range that is reached in vivo by convulsant doses. Only isoniazid inhibited the activity of GABA-T in vivo as well as in vitro. 2. Phenobarbital, ethosuximide and trimethadione were about equally active in preventing convulsions induced by strychnine and picrotoxin, whereas diazepam was 9 times, and sodium valproate 3.5 times more active against convulsions elicited by picrotoxin. Phenytoin up to 100 mg/kg was ineffective against all chemoconvulsants. 3. Diazepam, sodium valproate, ethosuximide and trimethadione antagonized the inhibition of GAD and the decrease in GABA concentrations caused by isoniazid. Phenobarbital and phenytoin prevented the decrease of GABA but did not reverse the inhibition of GAD. 4. The results suggest a role played by the transmitter pool of GABA in the convulsant action of chemoconvulsants and in the anticonvulsant effect of antiepileptics clinically used in petit mal epilepsy.

4-Aminobutyrate Transaminase↗
PubMed1990

Gamma-aminobutyric acid concentration in lumbar cerebrospinal fluid from patients with febrile convulsions and controls.

The cerebrospinal fluid (CSF) concentration of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) was analysed in 41 children with febrile convulsions (FC), 41 febrile controls of similar age (control group 1), and 59 controls, who had no fever and/or were outside the age range for FC (control group 2). A significant correlation between CSF-GABA and age was demonstrated for controls (1 + 2) (r = 0.63, p less than 0.00001), as well as for patients with FC (r = 0.42, p = 0.003). Patients with FC did not differ significantly from control group 1 in respect to CSF-GABA. Duration of FC was related to both CSF-GABA and age (GABA: r = -0.29, p less than 0.05; age: r = -0.32, p less than 0.05). For 56 controls (1 + 2) greater than 1 year of age, a significant negative correlation between CFC-GABA and body temperature was found (r = -0.34, p = 0.01). The low CSF-GABA in the FC-labile age group, the negative correlation of CSF-GABA to body temperature, and the negative correlation of the duration of FC to both CSF-GABA and age, all indicate that GABA could be of importance in the pathophysiology of FC.

Adolescent↗
PubMed2002

Immunoreactivity against choline acetyltransferase, gamma-aminobutyric acid, histamine, octopamine, and serotonin in the larval chemosensory system of Dosophila melanogaster.

We have studied the distribution of choline acetyltransferase (ChAT), gamma-aminobutyric acid (GABA), histamine, octopamine and serotonin in the larval chemosensory system of Drosophila melanogaster. Colocalization at the confocal level with green fluorescent protein (GFP) or Tau-GFP reporters, expressed in selected P[GAL4] enhancer trap lines, was used to identify the cells making up these neurotransmitters. As in the adult fly, larval olfactory afferents project into the (larval) antennal lobe (LAL), where they synapse onto local interneurons and projection neurons, whereas gustatory afferents terminate essentially in the tritocerebral-subesophageal (TR-SOG) region. We demonstrate that the neuropils of the LAL and the TR-SOG are immunoreactive to ChAT and GABA. In addition, serotonin- and octopamine-immunoreactive fibers are present in the LAL. ChAT immunostaining is localized in subsets of olfactory and gustatory afferents and in many of the projection neurons. In contrast, GABA is expressed in most, and perhaps all, of the local interneurons. Serotonin immunoreactivity in the LAL derives from a single neuron that is situated close to the LAL and projects to additional neuropil regions. Taken together, these findings resemble the situation in the adult fly. Hence, given the highly reduced numbers of odorant receptor neurons in the larva, as shown in a previous study (Python and Stocker [2002] J. Comp. Neurol. 445:374-387), the larval system may become an attractive model system for studying the roles of neurotransmitters in olfactory processing.

Animals↗
PubMed1990

Oestrogen modulation of excitatory A1 noradrenergic input to rat medial preoptic gamma aminobutyric acid neurones demonstrated by microdialysis.

The effect of A1 cell group electrical stimulation on the simultaneous release of endogenous noradrenaline (NA) and gamma-aminobutyric acid (GABA) from the medial preoptic area (MPOA) was monitored with microdialysis. In ovariectomised (OVX) rats a 15-min period of A1 stimulation induced an immediate increase in both NA and GABA release in the MPOA. Electrical stimulation lateral to the A1 region did not alter NA or GABA release. The addition of the alpha-adrenergic antagonist phenoxybenzamine to the perfusion medium resulted in a significant increase in basal NA levels, and electrical stimulation during this period further increased NA release while GABA levels were not significantly altered throughout. The effect of oestrogen on this pathway was examined in animals at a time of oestrogen-negative feedback on luteinising hormone (LH) secretion (OVX-EBn) and prior to the expected oestrogen-induced LH surge (OVX-EBp). Activation of A1 neurones in OVX-EBn rats resulted in NA and GABA increases in the MPOA similar to that observed with OVX rats. In OVX-EBp animals, basal GABA levels were found to be significantly higher compared with OVX rats but NA release induced by A1 stimulation had no effect on GABA levels. Depolarisation of the MPOA by increasing the potassium ion concentration of the perfusion medium evoked significantly greater GABA release from OVX-EBp rats compared with the OVX and OVX-EBn animals. Potassium-stimulated NA release was not significantly altered by oestrogen administration. These results demonstrate an excitatory alpha-adrenergic mediated noradrenergic input to GABA neurones in the MPOA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Evidence for gamma-aminobutyric acid modulation of ovarian hormonal effects on luteinizing hormone secretion and hypothalamic catecholamine activity in the female rat.

Recent evidence suggests that gamma-aminobutyric acid (GABA)-containing neurons may inhibit LH release under certain circumstances. The present experiments tested whether GABA agonists block the LH surge induced in ovariectomized rats by estradiol benzoate (EB) plus progesterone (P) treatment and whether these agents affect the concentration and turnover of hypothalamic catecholamines, assessed from the depletion that occurs after synthesis inhibition. Ovariectomized rats received EB, followed 2 days later by P. Simultaneously with P, rats received either saline or one of the GABA agonists, baclofen or muscimol. Other agonist-treated rats received a second injection 4 h later or were additionally treated with the postsynaptic GABA antagonist bicuculline. Additional experiments tested the effects of these agents on LH release in response to exogenous LHRH. The LH surge induced by EB plus P was blocked by administration of either baclofen or muscimol in a dose-dependent manner. Bicuculline did not prevent the effect of baclofen, but partially prevented the effect of muscimol. Neither baclofen nor muscimol significantly affected LH release in rats receiving LHRH. In a second set of studies in EB plus P-treated rats, baclofen and muscimol decreased the steady state concentrations of norepinephrine in the medial preoptic area and medial basal hypothalamus for several hours and markedly decreased the turnover rate of norepinephrine in these areas. The concentrations and turnover of epinephrine were also decreased by these GABA agonists in the medial basal hypothalamus. The drugs had no effect on dopamine levels or turnover in either structure. These results support the hypothesis that a GABAergic system regulates LH release via modulation of noradrenergic and adrenergic systems that control LHRH secretion.

Animals↗
PubMed1978

Receptors for gamma-aminobutyric acid (GABA) on Aplysia neurons.

Aplysia neurons show 5 different types of response (three excitatory and two inhibitory) to iontophoretic application of gamma-aminobutyric acid (GABA). Four of these are associated with a membrane conductance increase, but one is associated with a conductance decrease. The most common response is a fast hyperpolarization which reverses at about--58 mV and is sensitive to manipulation of external Cl- concentration, and thus is due to a specific increase in Cl- conductance. There is an infrequent, slower hyperpolarizing response which does not reverse above about--80 mV and is insensitive to external Cl-. This response appears to result from a conductance increase to K+. Two types of depolarizing responses are associated with conductance increases. These responses differ in their latency, duration and sensitivity to curare. The more frequent is relatively rapid (peak at 1-2 sec) and is depressed by curare at high concentrations. In other neurons, GABA causes a slower response, peaking at 6-10 sec, which is not curare-sensitive. Usually for both types of response, the voltage and conductance changes are completely abolished by perfusion with Na+-free seawater, and the responses cannot be reversed with depolarization. In other neurons such as L11, the response can be reversed with depolarization, and appears to result from a conductance increase to both Na+ and Cl-. In neuron R15, GABA causes a slow depolarizing response (peak at about 9 sec) which is associated with a decreased membrane conductance, probably to K+. The classical GABA antagonists, picrotoxin and bicuculline, block Cl- responses but no others, while the fast Na+ and Cl- responses are depressed by curare. Strychnine does not affect any GABA response. The multiplicity of GABA responses, the specificity of their organization and the fact that only some neurons have receptors for GABA, argue that GABA may have a role as a neurotransmitter in Aplysia. Furthermore, the existence of several types of excitatory GABA response suggests that GABA may function both as an inhibitory and excitatory neurotransmitter.

Acetylcholine↗
PubMed1986

In vivo release of [3H]gamma-aminobutyric acid in the rat neostriatum--I. Characterization and topographical heterogeneity of the effects of dopaminergic and cholinergic agents.

The release of [3H]gamma-aminobutyric acid continuously synthesized from [3H]glutamine was studied in the striatum of halothane-anaesthetized rats superfused with a push-pull cannula. The levels of spontaneously released [3H]GABA were identical in all striatal regions examined, but were found to be higher at the junction between the striatum and the globus pallidus. Superfusion with a medium enriched in K+ ions induced a concentration-dependent increase in [3H]GABA release. Superfusion with a Ca2+-free medium did not affect the spontaneous outflow of [3H]GABA but sharply reduced the release of [3H]GABA evoked by 30 mM K+. Locally applied tetrodotoxin (50 microM) decreased slightly the spontaneous release of [3H]GABA (-22%). When acetylcholine (50 or 500 microM) was added to a superfusion medium containing eserine (50 microM), the spontaneous release of [3H]GABA was enhanced in the ventral but not in the dorsal region of the striatum. The local application of 2,3,4,5-tetrahydro, 7,8,-dihydroxy, 1-phenyl, 1-H, 3-benzazepine (10 microM), a dopaminergic agonist acting preferentially on D1 receptors increased the release of [3H]GABA in the dorsal striatum (+32%) but decreased it slightly (-19%) in the ventral striatum. 3-(2-(N-3 hydroxyphenylethyl)N-propylamino)ethyl-phenol (50 microM), a preferential D2 receptor agonist, decreased [3H]GABA release when it was applied dorsally (-23%) but not ventrally in the striatum. It is concluded that the regulation of the release of [3H]GABA by acetylcholine and dopaminergic drugs is different in the dorsal and ventral regions of the striatum. These differences may be related to the existence of subpopulations of GABA neurons and may well have functional implications as suggested by behavioural studies.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2003

Gamma-aminobutyric acid as a promoting factor of cancer metastasis; induction of matrix metalloproteinase production is potentially its underlying mechanism.

We investigated expression of gamma-aminobutyric acid (GABA), glutamate decarboxylase, and matrix metalloproteinase (MMP) in the prostates of patients with cancer or benign prostatic hypertrophy by immunohistochemical study. Marked expression of GABA, glutamate decarboxylase 67, and MMPs was observed in the prostates of cancer patients with metastasis (n = 72) and lymph node metastasis, although only sparse expression was noted in those of cancer patients without metastasis (n = 76) or patients with benign prostatic hypertrophy (n = 152). We then investigated the influence of GABA stimulation on in vitro MMP production and the invasive ability of cancer cells using human prostate cancer cell line C4-2. The production of MMPs increased significantly in cancer cells after a 24-h incubation with GABA. Cell invasion assay using a BioCoat Matrigel Invasion Chamber kit revealed that GABA stimulation significantly promoted the invasive ability of cancer cells and that addition of MMP inhibitor GM6001 significantly decreased GABA-induced migration. This may indicate the involvement of MMP activity in GABA-induced cancer cell invasion. We further analyzed the transmission pathway by performing GABA receptor modulation. The GABA(B) receptor agonist baclofen significantly increased MMP production as well as invasive ability. Moreover, blockade of the GABA(B) receptor pathway using GABA(B) receptor antagonist CGP 35348 significantly inhibited GABA-induced MMP production and invasive ability in cancer cells, whereas GABA(A) receptor modulation did not influence MMP production or the invasive ability of cancer cells. Thus, increased expression of GABA may be implicated in cancer metastasis by promoting MMP production in cancer cells, and the GABA(B) receptor pathway may be involved in the process.

Aged↗
PubMed1983

[3H]bicuculline methochloride binding to low-affinity gamma-aminobutyric acid receptor sites.

The binding of [3H]bicuculline methochloride (BMC) to mammalian brain membranes was characterized and compared with that of [3H] gamma-aminobutyric acid ([3H]GABA). The radiolabeled GABA receptor antagonist showed significant displaceable binding in Tris-citrate buffer that was improved by high concentrations of chloride, iodide, or thiocyanate, reaching greater than 50% displacement in the presence of 0.1 M SCN-. An apparent single class of binding sites for [3H]BMC (KD = 30 nM) was observed in 0.1 M SCN- for fresh or frozen rat cortex or several regions of frozen and thawed bovine brain. The Bmax was about 2 pmol bound/mg of crude mitochondrial plus microsomal membranes from unfrozen washed and osmotically shocked rat cortex, similar to that for [3H]GABA. Frozen membranes, however, showed decreased levels of [3H]BMC binding with no decrease or an actual increase in [3H]GABA binding sites. [3H]BMC binding was inhibited by GABA receptor specific ligands, but showed a higher affinity for antagonists and lower affinity for agonists than did [3H]GABA binding. Kinetics experiments with [3H]GABA binding revealed that low- and high-affinity sites showed a similar pharmacological specificity for a series of GABA receptor ligands, but that whereas all agonists had a higher affinity for slowly dissociating high-affinity [3H]GABA sites, bicuculline had a higher affinity for rapidly dissociating low-affinity [3H]GABA sites. This reverse potency between agonists and antagonists during assay of radioactive antagonists or agonists supports the existence of agonist- and antagonist-preferring conformational states or subpopulations of GABA receptors. The differential affinities, as well as opposite effects on agonist and antagonist binding by anions, membrane freezing, and other treatments, suggest that [3H]BMC may relatively selectively label low-affinity GABA receptor agonist sites. This study, using a new commercially available preparation of [3H]bicuculline methochloride, confirms the report of bicuculline methiodide binding by Möhler and Okada (1978), and suggests that this radioactive GABA antagonist will be a valuable probe in analyzing various aspects of GABA receptors.

Animals↗
PubMed1992

On the inhibitory actions of baclofen and gamma-aminobutyric acid in rat ventral midbrain culture.

1. Whole-cell voltage-clamp recordings were used to study the effects of (-)-baclofen and of gamma-aminobutyric acid (GABA) on neurones cultured from the ventral midbrain of embryonic rats. 2. Baclofen induced an outward current (IBac) at a holding potential of -60 mV. The maximal current was 80 pA, and half-maximal current was evoked by 5 microM-baclofen. The proportion of cells affected by baclofen was greater in 25-day-old cultures than in 14-day-old cultures. 3. IBac was blocked by barium (1 mM), and it reversed polarity at a potential that changed according to the Nernst equation when the extracellular potassium concentration was changed. The reversal potential was not different when recording electrodes contained caesium instead of potassium. 4. GABA (10-20 microM), in the presence of picrotoxin (50 microM) and bicuculline (50 microM), also evoked a small potassium current at -60 mV. There was no correlation between the amplitude of the potassium current caused by GABA and that caused by baclofen measured in the same neurones. 5. Spontaneous synaptic currents (up to hundreds of picoamps) were observed that were blocked by picrotoxin (20 microM; IPSCs) or by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM; EPSCs); the amplitude and frequency were strongly reduced by baclofen and by GABA. 6. Spontaneous synaptic currents of lower amplitudes (up to 60 pA) remained in the presence of tetrodotoxin. IPSCs (blocked by picrotoxin, reversal at -50 mV) and EPSCs (blocked by CNQX, reversal at 0 mV) were reduced in frequency by baclofen. GABA, in the presence of bicuculline and picrotoxin, had a similar effect on the EPSCs. This action of baclofen persisted in barium (1 mM), and was observed as readily in cells cultured for 14 days as those cultured for 25 days. 7. Some spontaneous synaptic currents remained in the presence of tetrodotoxin and cadmium (100 microM). Their frequency was reduced by baclofen. The effectiveness of baclofen was greater on cells that had been longer in culture. 8. It is concluded that activation of GABAB receptors has two main effects on neurones cultured from rat ventral midbrain. These are potassium conductance increase, and inhibition of the spontaneous release of GABA and excitatory amino acids; both effects can be observed in tetrodotoxin and cadmium.

Animals↗
PubMed1989

Different gamma-aminobutyric acid receptor subtypes are involved in the regulation of opiate-dependent and independent luteinizing hormone-releasing hormone secretion.

The neurotransmitter gamma-aminobutyric acid (GABA) appears to be involved in the control of gonadotropin secretion. These studies were conducted 1) to evaluate the effect of GABAergic drugs on in vitro LHRH secretion and 2) to characterize the role of different types of GABA receptors (the GABA-A and GABA-B subtypes) in these actions. Arcuate nuclei-median eminence fragments were incubated in vitro, and the release of LHRH, prostaglandin E2 (PGE2), arginine vasopressin, and oxytocin was measured by RIA. Both GABA and muscimol at different concentrations induced an increase in LHRH release, but did not affect the release of arginine vasopressin and oxytocin. This stimulatory effect was blocked by the specific GABA antagonist bicuculline, suggesting the involvement of GABA-A type receptors. Muscimol-stimulated LHRH release was not affected by the presence of phentolamine, suggesting that the stimulatory effect of GABA-A receptors on LHRH release is not mediated by interactions with the noradrenergic system. PGE2 has been shown to be a potent secretagogue of LHRH from the median eminence in vitro, and in this model the stimulatory effect of PGE2 was enhanced by muscimol. Baclofen, a specific GABA-B type receptor agonist, had no effect on basal LHRH release, but completely suppressed naloxone-stimulated LHRH and PGE2 secretion. The inhibitory effect of baclofen was blocked by the presence of 5-aminovalerate, a drug that has been shown to block the inhibitory effect of baclofen on NE release from noradrenergic terminals. This suggests the possibility that GABA-B receptors interacting with noradrenergic terminals may be responsible for the inhibitory effect of baclofen on naloxone stimulation. This study uncovered both stimulatory and inhibitory effects of GABA on LHRH release after activation of GABA-A or GABA-B receptors, respectively. Further, the data show possible relationships among the GABAergic, endogenous opiate peptide, and noradrenergic systems in the control of LHRH release from the hypothalamus.

Animals↗
PubMed1996

Properties of recombinant gamma-aminobutyric acid A receptor isoforms containing the alpha 5 subunit subtype.

The cDNAs encoding alpha 5 and gamma 2L subunit subtypes of the gamma-aminobutyric acid (GABA) type A receptor (GABAR) were transfected into L929 cells together with cDNAs encoding either the beta 1, beta 2, or beta 3 subunit subtype. Properties of expressed recombinant alpha 5 beta X gamma 2L (where X = 1,2, or 3) GABARs were studied with the use of whole-cell, patch-clamp techniques. In cells voltage-clamped at -70 mV with equlvalent bath and pipette chloride concentrations, the application of GABA produced a concentration-dependent inward chloride current with all three alpha 5 beta X gamma 2L isoforms. Minimal or no responses were recorded from cells transfected with only two subunit cDNAs, demonstrating that all three subunits were required for functional receptor assembly in these cells. The GABA concentration producing a half-maximal current was similar for beta 2 and beta 3 subtype-containing receptors (6 microM) but higher for beta 1 subtype-containing receptors (26 microM). alpha 5 beta 3 gamma 2L receptors were zinc and diazepam sensitive but zolpidem insensitive. In response to low GABA concentrations, beta 1 and beta 3 subtype-containing receptors showed outward rectification of the current-voltage relationship, whereas current-voltage responses of beta 2 subtype-containing receptors were relatively linear. Likewise, at high GABA concentrations, beta 1 and beta 3 subtype-containing receptors showed less desensitization at positive than at negative membrane potentials. Beta 2 subtype-containing receptors displayed faster desensitization at depolarized potentials. These voltage-dependent properties were characteristic of alpha 5 but not alpha 1 or alpha 6 subtype-containing receptors and were similar to responses recorded from hippocampal CA1 pyramidal neurons. Based on the pharmacological and biophysical similarities to hippocampal GABAR responses, the alpha 5 beta 3 gamma 2L isoform could represent a native GABAR subtype.

Animals↗
PubMed2004

Kinetics of glutamate and gamma-aminobutyric acid in cerebrospinal fluid in a canine model of complex partial status epilepticus induced by kainic acid.

An imbalance of excitatory and inhibitory transmitters in the brain has been suggested to cause epileptic seizures. In this study, we investigated the kinetics of glutamate (GLU) and gamma-aminobutyric acid (GABA) in cerebrospinal fluid (CSF-GLU and CSF-GABA, respectively) using a high performance liquid chromatography (HPLC) in a canine model of complex partial status epilepticus (CPSE) induced by the microinjection of kainic acid (KA) into the unilateral amygdala. During the acute phase (3, 6, 12 and 48 hr after the onset of CPSE), CSF-GLU was significantly increased, while CSF-GABA was decreased, although not significantly. In the chronic phase, both CSF-GLU and CSF-GABA were significantly lower than normal at 72 hr after the onset of CPSE, and their levels returned to normal at 2 months. Results of the present study demonstrate that CSF-GLU is gradually increased in relation with seizure severity, and suggested the possibility that CSF-GABA was consistently decreased during CPSE induced by KA in dogs.

Animals↗
PubMed1981

gamma-aminobutyric acid in the murine brain: mass fragmentographic assay method and post-mortem changes.

An improved mass fragmentographic assay method for the determination of gamma-aminobutyric acid (GABA) in the brain is described. Applicability of the method was examined in a study of the effect of semicarbazide on GABA levels and in a separate study to confirm post-mortem increase in GABA. The method itself is based on Cattabeni's procedure in which GABA is assayed as trimethylsilyl derivative. Three improvements were made: a) application of a more suitable mass spectrometry system for GABA determination; b) use of 6-aminocaproic acid as the internal standard; c) selection f a high intensive ion (m/z 174) for mass fragmentographic analysis. The mass spectrometer used is accurate to as little as 25 pg. GABA levels after semicarbazide treatment decreased 54.4% in rat whole brain and 44.2% in the dorsal hippocampus. Rapid post-mortem increases in GABA levels were confirmed by application of the improved assay method; decreases were most clearly observable following microwave irradiation. Post-mortem changes in GABA were observed within 3 min after death, as reported by other researchers.

Amino Acids↗
PubMed1999

The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gamma-aminobutyric acid.

The stiff-person syndrome, a rare and disabling disorder, is characterized by muscle rigidity and episodic spasms that involve axial and limb musculature. Continuous contraction of agonist and antagonist muscles caused by involuntary motor-unit firing at rest are the hallmark clinical and electrophysiologic signs of the disease. Except for global muscle stiffness, results of neurologic examination are usually normal. Results of conventional computed tomography and magnetic resonance imaging of the brain are also normal. The cause of the stiff-person syndrome is unknown; however, an autoimmune pathogenesis is suspected because of 1) the presence of antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA); 2) the association of the disease with other autoimmune conditions; 3) the presence of various autoantibodies; and 4) a strong immunogenetic association. Anti-GAD antibodies, which are found in high titers in most patients, seem to be directed against conformational forms of GAD. New evidence suggests that these antibodies may be pathogenic because they interfere with the synthesis of GABA. In addition, a reduction in brain levels of GABA, which is prominent in the motor cortex, has been demonstrated with magnetic resonance spectroscopy in patients with the stiff-person syndrome. The stiff-person syndrome is clinically elusive but potentially treatable and should be considered in patients with unexplained stiffness and spasms. Drugs that enhance GABA neurotransmission, such as diazepam, vigabatrin, and baclofen, provide mild to modest relief of clinical symptoms. Immunomodulatory agents, such as steroids, plasmapheresis, and intravenous immunoglobulin, seem to offer substantial improvement. Results of an ongoing controlled trial will elucidate the role of these agents in the treatment of the disease.

Adjuvants, Immunologic↗