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PubMed2001

Evidence for a role for GABA(A) and NMDA receptors in ethanol inhibition of long-term potentiation.

We have investigated the mechanisms by which acute ethanol inhibits the induction of long-term potentiation (LTP) in area CA1 of the rat hippocampal slice. In a previous report [Alcohol. Clin. Exp. Res. 21 (1997) 404] we demonstrated that ethanol produces only a modest inhibition of pharmacologically isolated N-methyl-D-aspartate receptors (NMDAR) in the CA1 region of the hippocampus. Moreover, this level of inhibition was not sufficient to account for ethanol's complete inhibition of LTP induction in this brain region. One possible explanation of these results is that we may have underestimated ethanol's ultimate effect on the NMDAR by focusing on pharmacologically isolated NMDAR responses. Ethanol might indirectly inhibit the NMDAR by, for example, potentiating the GABA(A)R. To explore this possibility, we first examined the effects of the GABA(A)R antagonist picrotoxin (PTX) and the allosteric GABA(A)R modulator flunitrazepam on NMDAR responses. We demonstrate that these modulators of GABA(A)R activity significantly affect the magnitude of synaptically evoked NMDAR responses. We next examined the effects of ethanol on NMDAR responses in the presence and absence of PTX. We see a significantly greater ethanol inhibition of the NMDAR when GABA(A)Rs are functional, i.e. in the absence of PTX. These data suggest that ethanol produces an inhibition of the NMDAR indirectly by affecting the GABA(A)R neurotransmission. Moreover, we found that ethanol inhibition of NMDAR activity, both directly through actions on the NMDAR, and indirectly, possibly through potentiation of GABA(A)R activity, is sufficient to account for ethanol's complete blockade of LTP induction.

Animals↗
PubMed2001

Okadaic acid and cyclosporin A modulate [(3)H]GABA release from rat brain synaptosomes.

Rat brain synaptosomes were used to investigate the effect of okadaic acid, an inhibitor of protein phosphatase 1 and 2A, and cyclosporin A, an inhibitor of protein phosphatase 2B (calcineurin), on [(3)H]GABA release. Release of [(3)H]GABA was evoked by 4-aminopyridine in the presence of calcium and by alpha-latrotoxin in the presence and absence of calcium. Pretreatment of synaptosomes with 1 microM okadaic acid reduced [(3)H]GABA release evoked by 4-aminopyridine by about 40%. The effect of alpha-latrotoxin on [(3)H]GABA release was stimulated by okadaic acid. This stimulation was equal in both media. The stimulating effect of 4-aminopyridine and alpha-latrotoxin on [(3)H]GABA release was activated when synaptosomes were pretreated with cyclosporin A. Activation of 4-aminopyridine-evoked [(3)H]GABA release was observed at 1 microM cyclosporin A, but the toxin effect was enhanced only when concentration of cyclosporin A was increased to 10 microM. The level of cyclosporin A activation depended on alpha-latrotoxin concentrations used - a higher stimulating effect of cyclosporin A was observed with lower toxin concentration. These results suggest that in calcium medium 4-aminopyridine- and alpha-latrotoxin-evoked [(3)H]GABA release was realized by different mechanisms.

4-Aminopyridine↗
PubMed2000

A simple polar deacetylated caloporoside derivative is a positive modulator of the GABA(A) chloride channel complex in cortical mammalian neurones.

Synthesis of octyl-O-beta-D-mannopyranoside, a caloporoside analogue was achieved by the activation of 2,3,4,6-rerra-O-benzyl-1-O-1',3'2'-dioxaphosphacyclohexane-a lpha,beta-D-mannopyranosyl-2-oxide with TMSOTf (Trimethyl silyl triflate) and subsequent debenzylation. At 100 microM the molecule significantly and reversibly increased the magnitude of GABA(A) currents evoked in cultured rat pyramidal neurones whilst concomitantly reducing the incidence of spontaneous synaptic activity. These results contradict earlier proposals that such molecules bind to the TBPS (tert-Butylbicyclophosphorothionate) site to block the chloride channel.

Acetylation↗
PubMed2002

N-Substituted 4-amino-3,3-dipropyl-2(3H)-furanones: new positive allosteric modulators of the GABA(A) receptor sharing electrophysiological properties with the anticonvulsant loreclezole.

1,4-Addition of benzylamine to 2(5H)-furanone followed by dialkylation of the 3-position with allylbromide gave (+/-)-4-benzyl-3,3-diallyl-2(3H)-furanone (8), which served as the intermediate for the synthesis of various N-substituted 4-amino-3,3-dipropyl-2(3H)-furanones (+/-)-9a-l. The compounds were evaluated for their capacity to potentiate or inhibit GABA-evoked currents in Xenopus laevis oocytes expressing recombinant alpha1beta2gamma2 GABA(A) receptors. The benzyl, ethyl, and allyl carbamates ((R)-9a (100 microM), (+/-)-9b (100 microM), (+/-)-9c (200 microM)) stimulated GABA currents by 279 +/- 47%, 426 +/- 8%. and 765 +/- 61%, respectively, while the phenylcarboxamide (+/-)-9f (200 microM) stimulated currents by 420 +/- 33%. Concentration-response studies showed that compound 9c was approximately twice as potent in stimulating GABA currents as alpha-EMTBL (2), the most potent 3,3-dialkylbutyrolactone known to date. On the other hand, the N-sulfonyl analogues were much less active or even inhibited GABA-evoked currents. In vitro radioligand displacement studies on rat brain membranes showed that these compounds did not bind to the benzodiazepine or GABA recognition sites of the GABA(A) receptor. However, these compounds generally weakly displaced [(35)S]-TBPS (approximately 50% displacement at 100 microM), though potencies did not correlate with GABA current potentiation. Results obtained with alpha1beta1 and mutant alpha1beta2N265S receptors, which compared to alpha1beta2 receptors are both much less sensitive to current stimulation produced by the anticonvulsant loreclezole, suggest that at least some of these aminobutyrolactones, (e.g., 9a, 9c), and interestingly also alpha-EMTBL, share stimulatory properties with loreclezole.

Allosteric Regulation↗
PubMed2001

Modulation of GABA-augmented norepinephrine release in female rat brain slices by opioids and adenosine.

GABAA receptor activation augments electrically-stimulated release of norepinephrine (NE) from rat brain slices. Because this effect is not observed in synaptoneurosomes, GABA probably acts on inhibitory interneurons to disinhibit NE release. To determine whether opioids or adenosine influence GABA-augmented NE release, hypothalamic and cortical slices from female rats were superfused with GABA or vehicle in the presence and absence of 10 microM morphine or 100 microM adenosine. GABA augments [3H]NE release in the cortex and hypothalamus. Morphine alone has no effect on [3H]NE release, but attenuates GABA augmentation of [3H]NE release in both brain regions. Adenosine alone modestly inhibits [3H]NE release in the cortex, but not in the hypothalamus. Adenosine inhibits GABA-augmented [3H]NE release in both brain regions. The general protein kinase inhibitor H-7, augments [3H]NE release in both brain regions and may have additive effects with GABA in cortical slices. These results implicate opioid and adenosine interneurons and possibly protein kinases in regulating GABAergic influences on NE transmission.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2002

Modulation of the GABA(A)-gated chloride channel by reactive oxygen species.

The accumulation of reactive oxygen species during cellular injury leads to oxidative stress. This can have profound effects on ionic homeostasis and neuronal transmission. Gamma-aminobutyric acid (GABA) neurotransmission is sensitive to reactive oxygen species, but most studies have indicated that this is due to alterations in GABA release. Here, we determined whether reactive oxygen species can alter GABA(A) receptor-gated Cl- channels in the adult hippocampus. First, we measured the effects of hydrogen peroxide on intracellular Cl- using UV laser scanning confocal microscopy and the Cl(-)-sensitive probe, 6-methoxy-N-ethylquinolium iodide (MEQ). Superfusion of adult rat hippocampal slices with hydrogen peroxide for 10 min decreased MEQ fluorescence (elevation in [Cl-]i) significantly in area CA1 pyramidal cell soma. Alterations in [Cl-]i were prevented by the vitamin E analog Trolox, an antioxidant that scavenges free radicals. After exposure of slices to hydrogen peroxide, the ability of the GABA agonist muscimol to increase [Cl-]i was attenuated. To determine if GABA(A) receptors were sensitive to oxidative insults, the effect of hydrogen peroxide on the binding of [35S]t-butylbicyclophosphorothionate (TBPS) to GABA-gated Cl- channels was measured using receptor autoradiography and homogenate binding assays. Hydrogen peroxide inhibited [35S]TBPS binding in a regionally selective manner, with the greatest inhibition in cerebral cortex, hippocampus and striatum, areas vulnerable to oxidative stress. Similarly, xanthine and xanthine oxidase, which generate superoxide radicals, reduced [35S]TBPS binding in these regions. The effect of hydrogen peroxide on [35S]TBPS binding was non-competitive and was prevented by Trolox and the iron chelator, deferoxamine. We conclude that reactive oxygen species may compromise GABA(A)-mediated neuronal inhibition via interaction with pre and postsynaptic sites. A reduction in GABA(A)-gated Cl- channel function during periods of oxidative stress may contribute to the development of neuronal damage.

Animals↗
PubMed1998

Intracellular calcium stores modulate miniature GABA-mediated synaptic currents in neonatal rat hippocampal neurons.

The whole-cell configuration of the patch clamp technique was used to record miniature gamma-aminobutyric acidA (GABAA) receptor-mediated currents (in tetrodotoxin, 1 microM and kynurenic acid 1 mM) from CA3 pyramidal cells in thin hippocampal slices obtained from postnatal (P) day (P6-9) old rats. Switching from a Ca2+-containing to a nominally Ca2+-free medium (in which Ca2+ was substituted with Mg2+, in the presence or in the absence of 100 microM EGTA) did not change significantly the frequency or amplitude of miniature events. Superfusion of thapsigargin induced a concentration-dependent increase in frequency but not in amplitude of tetrodotoxin-resistant currents that lasted for the entire period of drug application. Mean frequency ratio (thapsigargin 10 microM over control) was 1.8+/-0.5, (n = 9). In nominally Ca2+-free solutions thapsigargin was ineffective. When bath applied, caffeine (10 mM), reversibly reduced the amplitude of miniature postsynaptic currents whereas, if applied by brief pressure pulses, it produced an increase in frequency but not in amplitude of spontaneous GABAergic currents. Superfusion of caffeine (10 mM) reversibly reduced the amplitude of the current induced by GABA (100 microM) indicating a clear postsynaptic effect on GABAA receptor. Superfusion of ryanodine (30 microM), in the majority of the cells (n = 7) did not significantly modify the amplitude or frequency of miniature events. In two of nine cells it induced a transient increase in frequency of miniature postsynaptic currents. These results indicate that in neonatal hippocampal neurons, mobilization of calcium from caffeine-ryanodine-sensitive stores facilitates GABA release.

Animals↗
PubMed1979

Phenobarbitone modulation of postsynaptic GABA receptor function on cultured mammalian neurons.

The anticonvulsant barbiturate phenobarbitone increases membrane current and conductance responses to gamma-aminobutyric acid (GABA) in cultured mouse spinal neurons. Analyses of GABA current fluctuations under control conditions and in the presence of phenobarbitone show that the principle action is to increase the average time during which GABA-activated channels remain open. The duration of minature synaptic currents with a time constant of decay similar to the mean open-time of GABA-activated channels is prolonged by the drug. The results suggest that (1) the synaptic events are GABA-mediated and (2) the enhancement of these events by barbiturate is due to the postsynaptic action of the drug.

Animals↗
PubMed1999

Muscarinic receptor modulation of GABA-mediated giant depolarizing potentials in the neonatal rat hippocampus.

1. The whole-cell patch clamp technique was used to study the role of muscarinic receptors in regulating the frequency of giant depolarizing potentials (GDPs) in CA3 hippocampal neurones in slices from postnatal (P) P1-P8 rats. 2. Atropine (1 microM) reduced the frequency of GDPs by 64.2 +/- 2.9 %. The acetylcholinesterase inhibitor edrophonium (20 microM) increased the frequency of GDPs in a developmentally regulated way. This effect was antagonized by the M1 muscarinic receptor antagonist pirenzepine. 3. In the presence of edrophonium, tetanic stimulation of cholinergic fibres induced either an enhancement of GDP frequency (179 +/- 79 %) or a membrane depolarization (27 +/- 16 mV) associated with an increase in synaptic noise. These effects were prevented by atropine. 4. Application of carbachol (3 microM) produced an increase in GDP frequency that at P5-P6 was associated with a membrane depolarization and an increase in synaptic noise. These effects were prevented by atropine, pirenzepine (3 microM) and bicuculline (10 microM). 5. In the presence of pirenzepine, carbachol reduced GDP frequency by 50 +/- 4 %. Conversely, in the presence of methoctramine (3 microM), carbachol enhanced GDP frequency by 117 +/- 4 %. 6. It is concluded that endogenous acetylcholine, through the activation of M1 receptors, enhances the release of gamma-aminobutyric acid (GABA), in a developmentally regulated way. On the other hand, carbachol exerts both an up- and downregulation of GABA release through the activation of M1 and M2 receptors, respectively.

Animals↗
PubMed1994

Inhibition by KF17837 of adenosine A2A receptor-mediated modulation of striatal GABA and ACh release.

1. The effect of the A2A adenosine receptor agonist, 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine (CGS 21680) on the potassium evoked release of [3H]-gamma-aminobutyric acid ([3H]-GABA) from nerve terminals derived from the caudate-putamen and the globus pallidus of the rat was compared. In both preparations CGS 21680 (1 nM) inhibited the [3H]-GABA release evoked by 15 mM KCl but had no effect on that evoked by 30 mM KCl. 2. The ability of CGS 21680 (1 nM) to inhibit the release of [3H]-GABA from striatal nerve terminals was unaffected by the presence of the GABA receptor antagonists, bicuculline (10 microM), phaclofen (100 microM) and 2-hydroxysaclofen (100 microM). Similarly the opioid receptor antagonist, naloxone (10 microM), the adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 40 nM), and the cholinoceptor antagonists, mecamylamine (10 microM) and atropine (100 nM) had no effect on this inhibition. 3. The ability of CGS 21680 (0.1 nM) to stimulate the release of [3H]-acetylcholine ([3H]-ACh) from striatal nerve terminals was unaffected by the presence of bicuculline (10 microM), 2-hydroxysaclofen (100 microM), phaclofen (100 microM), naloxone (10 microM) and DPCPX (4 nM). 4. The novel A2A receptor antagonist, (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF 17837), blocked the CGS 21680 (1 nM)-induced inhibition of [3H]-GABA efflux with an EC50 of approximately 30 nM and also antagonized the CGS 21680 (0.1 nM)-induced stimulation of [3H]-ACh release with an EC50 of approximately 0.3 nM. 5. It is concluded that the A2A adenosine receptor is present on both GABAergic and cholinergic nerve terminals of the rat striatum and that in both the caudate-putamen and the globus pallidus this receptor inhibits [3H]-GABA release. No evidence was seen for a difference in the ligand binding sites of this receptor in the two groups of nerve terminals.

Acetylcholine↗
PubMed1991

Modulation of GABA-gated chloride currents by intracellular Ca2+ in cultured porcine melanotrophs.

1. The modulatory role of intracellular Ca2+ concentration ([Ca2+]i) on gamma-aminobutyric acid type A (GABAA) receptor-gated Cl- currents was investigated in dialysed and intact cells of cultured porcine pituitary intermediate lobe (IL) cells using the patch-clamp technique. In order to isolate Ca2+ and Cl- currents all other membrane currents were blocked pharmacologically. Isoguvacine, a specific GABAA receptor agonist, was used to activate selectively GABAA receptor-mediated whole-cell and single-channel Cl- currents. 2. In the whole-cell recording (WCR) configuration inward Ca2+ currents triggered before and/or during the application of isoguvacine (100 microM), did not inhibit the GABAA receptor-mediated response. This lack of effect of calcium currents was obtained in all situations tested, i.e. when the intracellular Ca2+ concentration was only weakly buffered (0.5 mM-EGTA in the pipette solution), not buffered at all (no EGTA added to the pipette solution) or when the resting [Ca2+]i was buffered at 10(-7) M (pCa 7) with internal EGTA. 3. At pCa 7, simultaneous application of isoguvacine (100 microM) and caffeine (10 mM) resulted in a 47 +/- 15% reduction of the whole-cell GABAA response. In the same conditions, a ten times lower concentration of caffeine (1 mM), induced a transient increase of the GABAA response which turned into a steady-state inhibition during the subsequent applications. 4. At pCa 7, when isoguvacine (100 microM) was applied together with 3Me-His2-TRH (50 nM), a potent analogue of the calcium-recruiting thyrotrophin-releasing hormone, the GABAA receptor-gated Cl- current was increased by 40 +/- 8%. In the absence of the Ca2+ chelator EGTA in the pipette solution, either potentiating or inhibitory effects of 3Me-His2-TRH on the GABAA response were observed. 5. If a high concentration (18 mM) of the calcium chelator EGTA was included in the pipette solution, caffeine and 3Me-His2-TRH had markedly lower effects on the GABAA response than those observed at pCa 7, suggesting that the effect of both substances was mediated by an increase in [Ca2+]i. 6. In the absence of extracellular Ca2+, the effects of caffeine and 3Me-His2-TRH were not significantly different from those obtained in the presence of Ca2+ (5 mM), suggesting that Ca2+ influx was not the major route for increasing [Ca2+]i. 7. In the cell-attached (CA) configuration, the presence of isoguvacine (3-5 microM) in the pipette solution triggered the opening of channels displaying multiple current levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Modulation of GABA-mediated synaptic transmission by endogenous zinc in the immature rat hippocampus in vitro.

1. Intracellular recordings from postnatal 2- to 12-day-old (P2-12) rat hippocampal CA3 pyramidal neurones exhibited spontaneous synaptic potentials mediated by GABAA receptors. These potentials can be separated on the basis of amplitude into two classes which are referred to as small and large. 2. The large depolarizing potentials were reversibly inhibited by the Zn2+ chelator 1,2-diethyl-3-hydroxypyridin-4-one (CP94). The small inhibitory postsynaptic potentials. (IPSPs) were apparently unaffected. 3. Stimulation of the mossy fibre pathway evoked composite excitatory postsynaptic potentials (EPSPs) and IPSPs. Threshold stimulus-evoked synaptic potentials were mediated by GABAA receptors and were reversibly blocked by CP94. The responses evoked by suprathreshold stimulation and persisting in the presence of bicuculline or CP94 were partially inhibited by 2-amino-5-phosphonopropionic acid (AP5) and were completely blocked with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). 4. L-Histidine, which preferentially forms complexes with Cu2+ > Zn2+ > Fe2+ > Mn2+, inhibited both naturally occurring spontaneous and evoked GABAA-mediated large synaptic potentials without affecting the neuronal resting membrane properties. Exogenously applied Zn2+ induced large spontaneous synaptic potentials and prolonged the duration of the evoked potentials. These effects were reversibly blocked by histidine. 5. The metal chelating agent diethyldithiocarbamate had little effect on the large amplitude synaptic potentials. 6. The transition metal divalent cations Fe2+ and Mn2+ did not initiate large synaptic potentials in CA3 neurones; however, Cu2+ depolarized the membrane and enhanced both excitatory and inhibitory synaptic transmission, resulting in a transient increase in the frequency of the large amplitude events. In comparison, zinc increased the frequency of the large potentials and also induced such events in neurons (P4-21) where innate potentials were absent. The postsynaptic response to ionophoretically applied GABA was either unaffected or slightly enhanced by Zn2+. 7. Under conditions favouring the activation of non-NMDA receptors, excitatory synaptic transmission was unaffected by CP94 but was depressed by Zn2+. Responses to ionophoretically applied glutamate were not inhibited by Zn2+, indicating that Zn2+ affects excitatory synaptic transmission via a presynaptic mechanism. 8. We conclude that the naturally occurring large synaptic potentials in young CA3 neurones are apparently induced by endogenous Zn2+ which can promote or synchronize the release of GABA in the immature hippocampus.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1986

Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.

Two metabolites of the steroid hormones progesterone and deoxycorticosterone, 3 alpha-hydroxy-5 alpha-dihydroprogesterone and 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone, are potent barbiturate-like ligands of the gamma-aminobutyric acid (GABA) receptor-chloride ion channel complex. At concentrations between 10(-7) and 10(-5)M both steroids inhibited binding of the convulsant t-butylbicyclophosphorothionate to the GABA-receptor complex and increased the binding of the benzodiazepine flunitrazepam; they also stimulated chloride uptake (as measured by uptake of 36Cl-) into isolated brain vesicles, and potentiated the inhibitory actions of GABA in cultured rat hippocampal and spinal cord neurons. These data may explain the ability of certain steroid hormones to rapidly alter neuronal excitability and may provide a mechanism for the anesthetic and hypnotic actions of naturally occurring and synthetic anesthetic steroids.

20-alpha-Dihydroprogesterone↗
PubMed1977

Presynaptic modulating effects of GABA on depression, facilitation, and posttetanic potentiation of a cholinergic synapse in Aplysia californica.

The effects of gamma-aminobutyric acid (GABA) have been studied on the synaptic depression, frequency facilitation, and posttetanic potentiation (PTP) of a unitary, monosynaptic, and presumably cholinergic excitatory postsynaptic potential (EPSP). This EPSP, produced by minimal stimulation of the right visceropleural connective, was recorded in cell R 15 of Aplysia californica. Perfusion with GABA (10(-4)-10(-3) M) reduces the size of all EPSPs produced by a train of 100 stimuli at 1/s. It also reduced the synaptic depression and PTP, and increases the frequency facilitation seen during the train. GABA does not significantly effect the membrane resistance (mean 102%) but it slightly depolarizes (mean 6 mV) the postsynaptic cell. GABA does not reduce an acetylcholine iontophoretic potential produced on R15. The effects of GABA are reduction when chloride is replaced by acetate but they remain significant. Picrotoxin and bicuculline fail to antagonize GABA. Addition of sodium azide or dinitrophenol does not reduce the action of GABA and even prolongs it. The effects of GABA are attributed to two sites of action: a postsynaptic one, responsible for the small change in potential and partially responsible for the reduction of EPSP size; and a presynaptic one, responsible for a further reduction of EPSP size and the changes of depression, facilitation, and PTP.

Acetylcholine↗
PubMed2002

Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults.

BACKGROUND: Anticonvulsant drugs have multiple mechanisms of action. Recent in vivo MRS studies suggest that cerebral gamma-aminobutyric acid (GABA) increases occur with the administration of certain anticonvulsants in humans. OBJECTIVE: To investigate the effect of topiramate, gabapentin, and lamotrigine on cerebral GABA concentrations in healthy volunteers and correlate the GABA concentrations with serum drug levels. METHODS: Seventeen healthy adults were randomly assigned to receive topiramate, gabapentin, and lamotrigine and underwent GABA measurements using a 4.1-T magnet from a 13.5-mL volume over the occipital region. GABA concentrations and serum levels were measured at 3 and 6 hours following administration of an acute single dose of one of the drugs. Thereafter, drugs were titrated over 4 weeks to target doses, with GABA measurements performed at 2 and 4 weeks. RESULTS: Cerebral GABA concentrations rose 70% in the acute phase compared with baseline for topiramate. GABA rose 48% at 6 hours with gabapentin but not with lamotrigine. With long-term dosing and once target doses were achieved at 4 weeks, significant elevations in GABA were observed compared with baseline for all three drugs (topiramate 46%, gabapentin 25%, lamotrigine 25%). CONCLUSION: This study demonstrates that single doses of topiramate and gabapentin increase cerebral GABA concentrations acutely (hours) in healthy individuals, but all drugs at clinically utilized doses increase cerebral GABA at 4 weeks. These results suggest that the mechanisms of action of anticonvulsant drugs are more complex and are likely to be multiple in nature.

Acetates↗