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PubMedDate not supplied

Aging does not alter the sensitivity of benzodiazepine receptors to GABA modulation.

The effects of GABA on benzodiazepine receptor binding in cerebral cortical, hippocampal, and cerebellar membranes from 2-3 months old and 28-32 months old rats were studied. GABA modulation of agonist, antagonist, and inverse agonist binding to the receptor was examined using the displacement of 3H-Ro15-1788 by diazepam, Ro15-1788, and beta-carboline-3-carboxylate methyl ester, respectively, in the absence and presence of 100 microM GABA and 150 mM sodium chloride. GABA modulation was alike in old and young rats, with respect to the particular ligand and brain region. The results support the hypothesis that, in the brain regions studied, the allosteric modulation of benzodiazepine receptor binding by GABA remains intact as a function of aging.

Aging↗
PubMed1997

Ondansetron modulates GABA(A) current of rat central nervous system neurons.

We examined the effect of ondansetron, a 5-HT3 receptor antagonist, on the whole cell current response of freshly isolated hypothalamic and hippocampal neurons of rats to gamma-aminobutyric acid (GABA). The nystatin perforated patch technique was used to minimize run-down of the GABA current. While 1-150 microM ondansetron had no effect on membrane conductance, co-application with agonist reversibly depressed the maximal end GABA current. The concentration-response relation of GABA reveals a non-competitive mechanism. However, the inhibitory effect was more potent when ondansetron was co-applied with lower concentrations of GABA: i.e., the ondansetron concentration needed to depress the current induced by 5 microM GABA to half amplitude was 7 microM compared to 28 microM for the current induced by 10 microM GABA. Analysis of the current-voltage relationship with and without ondansetron indicated that the effect of ondansetron is not voltage dependent. Current-voltage relations also showed that the effect of ondansetron was not due to activation of a GABA-independent current because the reversal potentials were the same with and without ondansetron. The present data suggest that ondansetron's suppression of GABA-activated current may be the molecular basis of ondansetron-induced seizures observed in vivo.

Animals↗
PubMed1996

Nitrooxy alkyl apovincaminate modulates GABA(A) receptor in rat neocortical neurones.

We investigated the effects of VA-045 ((+)-eburnamenine-14 carboxylic acid (2-nitroxyethyl) ester) on GABA(A) receptor-mediated Cl- currents in dissociated rat cerebral cortical neurones, using a nystatin-perforated patch recording configuration. At a holding potential of - 40mV, the external application of GABA evoked an inward Cl- current with an EC50 value of 5.6 x 10(-6)M. VA-045 increased the GABA response at GABA concentrations below 3.0 x 10(-6)M. The GABA response showed a time dependent decay consisting of fast and slow components and VA-045 significantly accelerated both components. The site of action for VA-045 was considered to be different from that for benzodiazepines or barbiturates.

Animals↗
PubMed2000

Conformationally constrained anesthetic steroids that modulate GABA(A) receptors.

Various cyclic ether and other 3 alpha-hydroxyandrostane derivatives bearing a conformationally constrained hydrogen-bonding moiety were prepared. Their anesthetic potency and their binding affinity for GABA(A) receptors, measured by intravenous administration to mice and inhibition of [(35)S]TBPS binding to rat whole brain membranes, were compared with that of known anesthetic 3 alpha-hydroxypregnan-20-ones. Synthetic steroids with similar in vitro and in vivo activities to the endogenous 3 alpha-hydroxypregnan-20-ones all had an ether oxygen on the beta-face of the steroid D-ring. These results suggest that for optimal GABA(A) receptor modulation, the hydrogen bond-accepting substituent should be near perpendicular to the plane of the D-ring on the beta-face of the steroid.

Androstanols↗
PubMed1995

Neuroactive steroids modulate GABA inhibition of hypothalamic somatostatin release.

The reduced steroids 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) and 3 alpha,21-di-hydroxy-5 alpha-pregnan-20-one (allotetrahydroDOC) are potent ligands of GABAA receptors. This study examined the possible modulatory effect of these metabolites on GABA inhibition of somatostatin release in cultured hypothalamic neurones. Allopregnanolone potentiates GABA inhibition, and reversed picrotoxin and bicuculline-induced augmentation of somatostatin release in a dose-dependent manner. AllotetrahydroDOC also inhibits the stimulated release induced by the antagonists, but did not modify that induced by depolarizing concentrations of K+. Pregnenolone sulphate had no effect on picrotoxin-induced somatostatin release. These findings clearly establish that 3 alpha-hydroxysteroids modulate GABA inhibition of hypothalamic somatostatin release.

Animals↗
PubMed1998

GABA modulates color-opponent bipolar cells in carp retina.

In the present work, the effects of gamma-aminobutyric acid (GABA) were examined while recording intracellularly from color-opponent bipolar cells in the isolated, superfused carp retina. Bath-applied GABA differentially suppressed light responses of R/G cells, which depolarized and hyperpolarized, respectively, in response to red and green flashes, and G/R cells, which showed the opposite responses. In either R/G or G/R cells, the response driven by input from red cones was invariably suppressed to a greater extent. Such effects of GABA were completely blocked by picrotoxin, but only partially by bicuculline, suggesting that the GABAC receptor, in addition to the GABAA receptor, may also be involved. It is postulated that GABA modulates the color-opponent bipolar cells either through activating GABA receptors on these cells directly or those on cone terminals indirectly.

Action Potentials↗
PubMed2002

Stress-induced deoxycorticosterone-derived neurosteroids modulate GABA(A) receptor function and seizure susceptibility.

Stress affects seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here, we provide evidence that GABA(A) receptor-modulating neurosteroids derived from deoxycorticosterone (DOC) play a role in stress-related changes in seizure control. DOC, an adrenal steroid whose synthesis is enhanced during stress, undergoes sequential metabolic reduction by 5alpha-reductase and 3alpha-hydroxysteroid oxidoreductase to form 5alpha-dihydrodeoxycorticosterone (DHDOC) and allotetrahydrodeoxycorticosterone (THDOC), a GABA(A) receptor-modulating neurosteroid with anticonvulsant properties. Acute swim stress in rats significantly elevated plasma THDOC concentrations and raised the pentylenetetrazol (PTZ) seizure threshold. Small systemic doses of DOC produced comparable increases in THDOC and PTZ seizure threshold. Pretreatment with finasteride, a 5alpha-reductase inhibitor that blocks the conversion of DOC to DHDOC, reversed the antiseizure effects of stress. DOC also elevated plasma THDOC levels and protected mice against PTZ, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, picrotoxin, and amygdala-kindled seizures in mice (ED50 values, 84-97 mg/kg). Finasteride reversed the antiseizure activity of DOC (ED50, 7.2 mg/kg); partial antagonism was also obtained with indomethacin (100 mg/kg), an inhibitor of 3alpha-hydroxysteroid oxidoreductase. Finasteride had no effect on seizure protection by DHDOC and THDOC, whereas indomethacin partially reversed DHDOC but not THDOC. DHDOC, like THDOC, potentiated GABA-activated Cl- currents in cultured hippocampal neurons (< or =1 microm) and directly activated GABA(A) receptor currents (> or =1 microm), compatible with a role for DHDOC in the antiseizure activity of DOC. DOC is a mediator of the physiological effects of acute stress that could contribute to stress-induced changes in seizure susceptibility through its conversion to neurosteroids with modulatory actions on GABA(A) receptors including THDOC and possibly also DHDOC.

5-alpha Reductase Inhibitors↗
PubMed1991

Very low concentrations of acetylcholine and GABA modulate transmitter responses.

Acetylcholine and GABA, at extremely low concentrations (10(-14) to 10(-8) M) which do not induce electrical responses, each modulate the chloride-dependent responses of Aplysia neurons to higher concentrations of the same transmitters. Low concentrations of acetylcholine cause a reduction of the response to both acetylcholine and GABA, while low concentrations of GABA cause a facilitation of responses to both acetylcholine and GABA. These effects have a clear threshold, are slow in onset, reversible with prolonged washing, and blocked by cooling.

Acetylcholine↗
PubMed2002

Activation of mGluR5 modulates GABA(A) receptor function in retinal amacrine cells.

Amacrine cells in the vertebrate retina receive glutamatergic input from bipolar cells and make synapses onto bipolar cells, ganglion cells, and other amacrine cells. Recent studies indicate that amacrine cells express metabotropic glutamate receptors (mGluRs) and that signaling within the inner plexiform layer (IPL) of the retina might be modulated by mGluR activity. This study tests the hypothesis that activation of mGluR5 modulates GABA(A) receptor function in retinal amacrine cells. Whole cell voltage-clamp recordings were combined with pharmacology to establish the identity of the ionotropic GABA receptors expressed in primary cultures of chick amacrine cells and to determine how mGluR5 activity affected the behavior of those receptors. Application of GABA (20 microM) produced currents that reversed at -58.2 +/- 0.9 mV, near the predicted Cl(-) reversal potential of -59 mV. The GABA(A) receptor antagonist, bicuculline (50 microM), completely blocked the GABA-gated currents. cis-4-Aminocrotonic acid (CACA; 100 microM), a GABA(C) receptor agonist, produced small currents that were not blocked by the GABA(C) antagonist, (1,2,5,6-tetrahydropyridine-4-yl) methylphosphinic acid (TPMPA; 20 microM), but were completely blocked by bicuculline. These results indicate that cultured amacrine cells express GABA(A) receptors exclusively. Activating mGluR5 with (RS)-2-chloro-5-hydroxyphenylglycine (CHPG; 300 microM) enhanced GABA-gated currents by 10.0 +/- 1.5%. Buffering internal Ca(2+) with BAPTA (10 mM) blocked the CHPG-dependent enhancement. Activation of PKC with the cell-permeable PKC activators (-)-7-octylindolactam V, phorbol 12-myristate 13 acetate (PMA), or 1-oleoyl-2-acetyl-sn-glycerol (OAG) also enhanced GABA-gated currents in a dose-dependent manner. Preactivation of PKC occluded the mGluR5-dependent enhancement, and inhibition of Ca-dependent PKC isotypes with Gö6976 (35 nM) suppressed the effects of mGluR5 activation, suggesting that mGluR5 and PKC are part of the same pathway. To determine if mGluR5-dependent enhancement occurred at synaptic GABA(A) receptors, postsynaptic currents were recorded in the presence of CHPG. On average, the mean amplitudes of the quantal events were increased by about 18% when mGluR5 was activated. These results indicate that activation of mGluR5 enhances GABA-gated current in cultured amacrine cells in a manner that is both Ca(2+)- and PKC-dependent. These results support the possibility that glutamate released from bipolar cells can modulate the function of GABAergic amacrine cells and alter signaling in the inner plexiform layer.

Amacrine Cells↗
PubMed2001

Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons.

Serotonergic neurotransmission in prefrontal cortex (PFC) has long been known to play a key role in regulating emotion and cognition under normal and pathological conditions. However, the cellular mechanisms by which this regulation occurs are unclear. In this study, we examined the impact of serotonin on GABA(A) receptor channels in PFC pyramidal neurons using combined patch-clamp recording, biochemical, and molecular approaches. Application of serotonin produced a reduction of postsynaptic GABA(A) receptor currents. Although multiple 5-HT receptors were coexpressed in PFC pyramidal neurons, the serotonergic modulation of GABA-evoked currents was mimicked by the 5-HT(2)-class agonist (-)-2,5-dimethoxy-4-iodoamphetamine and blocked by 5-HT(2) antagonists risperidone and ketanserin, indicating the mediation by 5-HT(2) receptors. Inhibiting phospholipase C blocked the 5-HT(2) inhibition of GABA(A) currents, as did dialysis with protein kinase C (PKC) inhibitory peptide. Moreover, activation of 5-HT(2) receptors in PFC slices increased the in vitro kinase activity of PKC toward GABA(A) receptor gamma2 subunits. Disrupting the interaction of PKC with its anchoring protein RACK1 (receptor for activated C kinase) eliminated the 5-HT(2) modulation of GABA(A) currents, suggesting that RACK1-mediated targeting of PKC to the vicinity of GABA(A) receptors is required for the serotonergic signaling. Together, our results show that activation of 5-HT(2) receptors in PFC pyramidal neurons inhibits GABA(A) currents through phosphorylation of GABA(A) receptors by the activation of anchored PKC. The suppression of GABAergic signaling provides a novel mechanism for serotonergic modulation of PFC neuronal activity, which may underlie the actions of many antidepressant drugs.

Animals↗
PubMed2000

GABA modulation of cocaine self-administration.

Recent experiments suggest that GABA compounds produce a clinically relevant modulation of cocaine reinforcement. This review summarizes the results of a number of studies that examined the effect of the GABAB agonist baclofen on cocaine self-administration using a variety of schedules of reinforcement. The results demonstrate that baclofen causes a dramatic reduction in cocaine self-administration which does not appear to be accounted for by a general disruption of behavior. However, the effect is dependent on the unit injection dose of cocaine and on the response requirements of the schedule. These results predict that in a clinical setting any potential therapeutic effect of baclofen will interact with the cost and availability of cocaine.

Animals↗
PubMed1988

Effect of norfloxacin, a new quinolone, on GABA modulation of TRH-induced TSH release from perifused rat pituitaries.

The effect of the quinolone norfloxacin, a new antibacterial agent that is thought to induce convulsions in patients by inhibiting the binding of GABA, was tested on the two kinds of GABA A modulation of fTRH-induced TSH release from perifused rat pituitaries. Norfloxacin (50 mumol/l) was found to reverse the inhibitory effect of GABA (100 nmol/l) on the TSH release induced by TRH (10 nmol/l). The ratio of induced over spontaneous release was 0.79 +/- 0.05 in the presence of GABA, and 2.32 +/- 0.18 when norfloxacin was added 15 min before GABA vs 2.59 +/- 0.09 in the control response to TRH. Norfloxacin was also able to reverse the potentiating effect of GABA (10 nmol/l): the TSH response was 6.56 +/- 0.94 in the presence of GABA alone vs 2.92 +/- 0.35 with norfloxacin plus GABA. Norfloxacin was also able to reverse the potentiation induced by isoguvacine, a specific GABA A agonist (6.15 +/- 1.14 in the presence of isoguvacine vs 2.99 +/- 0.54 with norfloxacin plus isoguvacine). Our results suggest that norfloxacin may antagonize the effect of GABA via the two classes of GABA A receptor sites which differ in affinity and are responsible for the dual effect of GABA on the TRH-induced TSH secretion.

Animals↗
PubMed2001

Dendrotoxin sensitive potassium channels modulate GABA but not glutamate release in the rat entorhinal cortex in vitro.

We have previously shown that the anticonvulsant drug, phenytoin, increases the frequency and amplitude of spontaneous inhibitory postsynaptic currents at GABA synapses on principal neurones in the rat entorhinal cortex. This effect is similar to that seen at other GABA synapses following blockade of voltage-gated potassium channels (Kv1.1, 1.2 and 1.6) with alpha-dendrotoxin. In the present study we examined whether dendrotoxins can alter GABA release at synapses in the entorhinal cortex. We recorded spontaneous inhibitory postsynaptic currents using whole cell voltage clamp techniques in slices of rat entorhinal cortex in vitro. alpha-Dendrotoxin evoked an increase in frequency and amplitude of spontaneous inhibitory postsynaptic currents, an effect that was blocked by prior perfusion with tetrodotoxin. The effect of the toxin did not occlude the increase in spontaneous inhibitory postsynaptic currents seen with phenytoin. Indeed, the effect of the two drugs together was, at least, additive on GABA release. Perfusion with the specific Kv1.1 blocker, dendrotoxin-K had no effect on GABA release. In addition, alpha-dendrotoxin had no effect on frequency or amplitude of spontaneous excitatory postsynaptic currents at glutamate synapses on entorhinal cortex neurones. We conclude that K-channels containing the Kv1.2 and/or 1.6 subunits modulate the release of GABA, but not glutamate in the entorhinal cortex. The modulation of GABA release by phenytoin is unlikely to be due to an effect on these channels.

Animals↗
PubMed1979

Stoichiometry of GABA-receptor interactions: GABA modulates the glycine-receptor interaction allosterically in a vertebrate neuron.

1. Measurement of steady-state conductance changes provides a reliable method for determination of transmitter-receptor stoichiometry in general and for GABA and its receptor interactions in particular. Log-log plotting of steady-state conductance changes as a function of decreasing transmitter concentration gives the molecularity of the interaction as a limiting slope. 2. Suitable measurements of GABA action in locust muscle show a molecularity of 3 with strong positive cooperativity. One molecule of picrotoxin is sufficient to block this reaction. Kinetic studies reveal the presence of occult desensitization. Thermodynamic studies reveal strong negative heats of interaction compatible with conformational changes in a multi-subunit receptor. 3. Measurements in the lateral dendrite of the goldfish Mauthner cell reveal that glycine has a more powerful action than GABA. Both interactions, however, utilize 4 molecules of amino acid with strong positive cooperativity to activate its receptors. The receptors are apparently distinct and there appears to be a higher glycine-receptor density. 4. In addition to its action on its own receptor, GABA allosterically modulates the glycine-receptor interaction in the Mauthner cell by lowering the energy barrier for the binding of the first glycine molecule, thereby increasing the affinity of glycine for its receptor.

Allosteric Regulation↗
PubMed2000

Plasma 5alpha-androstane-3alpha,17betadiol, an endogenous steroid that positively modulates GABA(A) receptor function, and anxiety: a study in menopausal women.

We tested the hypothesis that changes in endogenous neuroactive steroids acting as positive allosteric modulators of gamma-aminobutyric acid (GABA)(A) receptors may be related to the menopause-associated mood alterations. The study sample consisted of twenty five drug-free menopausal women, 1-3 years since the onset of menopause, homogeneous for age and body mass index (BMI) and without personal history of psychiatric, metabolic or endocrine disorders. Depression and anxiety-related symptoms were assessed with the Zung Self-administered Depression Scale (ZSDS) and the Cornell's Dysthymia Rating Scale (CDRS). The cut-off value predicted by the ZSDS index defined two groups of women (asymptomatic [35.5+/-4.6, n=12] and symptomatic [60.8+/-7.9, n=13]), that were also significantly different according to the CDRS scores (10.6+/-3.4 and 31.5+/-12, respectively, P<0.05). Upon evaluation of the scores relative to the anxiety factor of the CDRS (items 11-15) the symptomatic, but not the asymptomatic, group showed a moderate level of anxiety. The plasma concentrations of several neuroactive steroids were measured, after extraction and HPLC purification, by radioimmunoassay with specific antisera. Only dehydroepiandrosterone and its metabolite 5alpha-androstane-3alpha,17betadiol (3alpha-ADIOL), a positive allosteric modulator of GABA(A) receptors, were significantly (P<0.05 and P<0.005) higher (+110% and +64%, respectively) in the asymptomatic group. A highly significant and negative correlation (r=-0.672, P=0.003) was found between the plasma 3alpha-ADIOL concentrations and the scores of the anxiety factor of the CDRS. These data suggest that endogenous 3alpha-ADIOL modulates the central GABAergic tone and that higher 3alpha-ADIOL concentrations could have a role in preventing the expression of anxiety in the asymptomatic women.

Anxiety↗
PubMed2001

Alpha-amino acid phenolic ester derivatives: novel water-soluble general anesthetic agents which allosterically modulate GABA(A) receptors.

In the search for a novel water-soluble general anesthetic agent the activity of an alpha-amino acid phenolic ester lead, identified from patent literature, was markedly improved. In addition to improving in vivo activity in mice, good in vitro activity at GABA(A) receptors was also conferred. Within the series of compounds good enantioselectivity for both in vitro and in vivo activity was found, supporting a protein-mediated mechanism of action for anesthesia involving allosteric modulation of GABA(A) receptors. alpha-Amino acid phenolic ester 19, as the hydrobromide salt Org 25435, was selected for clinical evaluation since it retained the best overall anesthetic profile coupled with improved stability and water solubility. In the clinic it proved to be an effective intravenous anesthetic in man with rapid onset of and recovery from anesthesia at doses of 3 and 4 mg/kg.

Allosteric Regulation↗
PubMed1993

Opioid and GABA modulation of accumbens-evoked ventral pallidal activity.

The principle output of the nucleus accumbens innervates the ventral pallidum and rostral substantia innominata. GABA and opioid peptides are among the neurotransmitter candidates for this projection. The goal of the present experiments was to delineate further the physiology and pharmacology of the accumbens projection to the ventral pallidum. The trans-synaptic responsiveness of ventral pallidal and rostral substantia innominata neurons to electrical stimulation of the nucleus accumbens was examined concurrently with the ability of microiontophoretically applied morphine (an opioid agonist), naloxone (an opioid antagonist) and bicuculline (a GABA antagonist) to modulate evoked responses. Accumbens stimulation altered the firing rate in 60% of the 132 neurons tested. Fifty-two percent of responding neurons exhibited simple excitations or inhibitions in response to accumbens stimulation, while 48% exhibited complex response sequences with two or more evoked components. Predominant responses consisted of a short latency (< 10 ms) and short duration (10 ms) excitation (51% of responding neurons) and an inhibition with a variable, onset latency and, duration (52% of responding neurons). Evoked responses often occurred within limited areas within the ventral pallidum suggesting that activation of descending afferents can influence discrete targets within the region. A large majority (> 80%) of neurons evoked by accumbens stimulation also exhibited a current-dependent and naloxone-sensitive increase in spontaneous firing to microiontophoretically applied morphine. Morphine shortened the duration of the accumbens-evoked, short latency excitation and attenuated the magnitude of the long-latency inhibition. Evoked responses in the presence of morphine were opposite to those observed with naloxone, but similar to bicuculline. Thus, opioid receptor activation may be functionally antagonistic to GABAergic neurotransmission in the ventral pallidum. The prominence of accumbens-evoked and morphine-sensitive neurons within the ventral pallidum corroborates the density of accumbens and opioid input to this brain region, and demonstrates that opioids serve as an important influence on neuronal activity and information processing in the ventral-striatopallidal pathway.

Action Potentials↗
PubMed1996

Endogenous GABA modulates histamine release from the anterior hypothalamus of the rat.

Using a microdialysis method, we investigated the effects of the nipecotic acid-induced increase in content of endogenous GABA on in vivo release of histamine from the anterior hypothalamus (AHy) of urethane-anesthetized rats. Nipecotic acid (0.5 mM), an inhibitor of GABA uptake, decreased histamine release to approximately 60% of the basal level. This effect was partially antagonized by picrotoxin (0.1 mM), an antagonist of GABAA receptors, or phaclofen (0.1 mM), an antagonist of GABAB receptors. These results suggest that histamine release is modulated by endogenous GABA through both GABAA and GABAB receptors. When the tuberomammillary nucleus, where the cell bodies of the histaminergic neurons are localized, was stimulated electrically, the evoked release of histamine from the nerve terminals in the AHy was significantly enhanced by phaclofen, suggesting that GABAB receptors may be located on the histaminergic nerve terminals and modulate histamine release presynaptically. On the other hand, picrotoxin caused an increase in histamine release to approximately 170% of the basal level, and this increase was diminished by coinfusion with D(-)-2-amino-5-phosphonopentanoic acid (0.1 mM), an antagonist of NMDA receptors. Previously, we demonstrated tonic control of histamine release by glutamate mediated through NMDA receptors located on the histaminergic terminals in the AHy. These results suggest the possible localization of GABAA receptors on glutamatergic nerve terminals and that the receptors may regulate the basal release of histamine indirectly.

2-Amino-5-phosphonovalerate↗