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PubMed2000

[Modulation of GABA-activated currents by oxytocin in rat dorsal root ganglion neurons].

Experiments were performed on freshly isolated dorsal root ganglion (DRG) neurons of rat. GABA(A)-activated currents were recorded using the whole-cell patch clamp technique. The majority of the neurons (48/52, 90.5%) were sensitive to GABA (10( 6)~10( 3) mol/L). Application of oxytocin (OT) induced outward membrane responses in 51.3% (20/39) of the neurons, no apparent responses in 43.6% (17/39) and inward responses in 5.1% (2/39). 10( 12), 10( 11), 10( 10) and 10( 9) mol/L OT increased 10( 4) mol/L GABA-activated currents to 24.1+/-7.6% (n=6), 33.4+/-6.9% (n=9), 40.2+/-6.5% (n=13) and 67.2+/-14.8% (n=5), respectively. After preapplication of OT, the Kd value for GABA(A)-activated currents decreased, while the response obtained at the maximum concentration increased. The results suggest that the enhancement of GABA-activated currents by OT may suppress primary sensory transmission by potentiating pre-synaptic inhibition of GABA.

Animals↗
PubMed1988

Modulation of GABA-gated chloride ion flux in rat brain by acute and chronic benzodiazepine administration.

gamma-Aminobutyric acid (GABA)-gated Cl- influx was studied in rat brain "microsacs." Midazolam caused a shift to the left of the GABA log dose-response curve. Pentobarbital produced a similar shift plus an increase in maximum response. Diazepam, flurazepam and desalkylflurazepam also enhanced GABA-gated Cl- flux. Their effects were blocked by Ro15-1788, a benzodiazepine antagonist. Acute diazepam pretreatment caused a shift to the left of the GABA dose-response curve but had no effect on the ability of benzodiazepines or pentobarbital to increase GABA-gated Cl- influx. In rats made tolerant by 4 weeks of flurazepam treatment, there was no decrease in the ability of GABA to mediate Cl- flux. GABA was more potent in microsacs from nonwithdrawn rats. In rats withdrawn for 12 but not 48 hr, the maximum GABA response was increased. The ability of benzodiazepines and of pentobarbital to enhance GABA-gated Cl- influx was reduced, showing tolerance. However, 2 days after withdrawal from chronic treatment, this was no longer statistically significant. The results show that benzodiazepine tolerance involves reduced functional coupling between the benzodiazepine recognition site and the GABA recognition site-Cl- channel. Furthermore, reduced effectiveness of GABAA agonists in benzodiazepine-tolerant animals might result from alterations in neuronal activity that occur subsequently to activation of the GABA receptor-gated anion channel.

Animals↗
PubMed1994

Volatile anesthetics bidirectionally and stereospecifically modulate ligand binding to GABA receptors.

Pharmacologically relevant concentrations of volatile anesthetics can bidirectionally modulate radioligand binding to GABAA receptors. In mouse cerebral cortex, halothane (a prototypic volatile anesthetic) increased [3H]muscimol (a GABA receptor agonist) binding while inhibiting the binding of a GABA receptor antagonist ([3H]SR 95531). These bidirectional effects of inhalational anesthetics on ligand binding to GABA receptors are effected through changes in the Bmax with no significant alterations in the KD of these radioligands. Moreover, the concentration dependent, bidirectional modulation of radioligand binding to GABA receptors by volatile anesthetics exhibited stereoselectivity. Thus, (+)-isoflurane was about twice as potent as the (-)-enantiomer in enhancing [3H]muscimol binding and approximately 50% more potent as an inhibitor of [3H]SR 95531 binding, respectively. The demonstration of a bidirectional, stereospecific modulation of radioligand binding to GABA receptors by inhalational agents is consistent with the presence of specific recognition sites for inhalational anesthetics on the GABAA receptor complex.

Animals↗
PubMed1996

8-Bromo-cAMP mimics beta-adrenergic sensitization of GABA responses to ethanol in cerebellar Purkinje neurons in vivo.

Previous studies in our laboratory indicated that electrophysiological responses of cerebellar Purkinje neurons to GABA were not routinely potentiated by ethanol (EtOH), and the potentiation was not large when it occurred. In the presence of beta-adrenergic agonists, such as isoproterenol, however, GABA inhibitions became sensitive to potentiation by EtOH in nearly every Purkinje neuron tested. beta-adrenergic receptor activation alone also modulates (potentiates) GABA responses on Purkinje neurons, and this has been reported to be mediated by a cAMP second messenger system. Herein, we report that the membrane-permeable cAMP analog, 8-bromoadenosine-3',5'-cyclic monophosphate (8-Br-cAMP), but not the membrane-impermeable cAMP, can also modulate GABA responses and that EtOH potentiates this facilitatory action of 8-Br-cAMP. These effects are not likely caused by adenosine receptor mechanisms, because this 8-bromoadenosine mediated modulation and sensitization was observed in the presence of systemic theophylline. These data suggest that the beta-adrenergic modulation and sensitization to EtOH of cerebellar Purkinje neuron GABA responses occur via a cAMP second messenger mechanism.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2006

GABA(A) and GABA(B) receptors differentially modulate volume and frequency in ventilatory compensation in obese Zucker rats.

The aim of this study was to investigate whether GABA(A) and/or GABA(B) receptor-mediated mechanisms contribute to the impaired ventilatory response and reduced maximal aerobic exercise capacity in obese Zucker rats. Ten lean and 10 obese Zucker rats were studied at 12 wk of age. Minute ventilation (Ve), tidal volume (Vt), and breathing frequency (f) during room air breathing and in response to 10 min of hypercapnia (8% CO(2)) and 30 min of hypoxia (10% O(2)) were measured by the barometric method, and peak oxygen consumption (Vo(2 peak)) was measured by an enclosed metabolic treadmill following the randomized blinded subcutaneous administration of equal volumes of DMSO (vehicle), bicuculline (selective GABA(A) receptor antagonist, 1 mg/kg), and phaclofen (selective GABA(B) receptor antagonist, 1 mg/kg). Administration of bicuculline and phaclofen to lean animals had no effect on Ve and Vo(2 peak). Similarly, phaclofen failed to alter Ve and Vo(2 peak) in obese rats, although it did significantly increase f after 5-20 min of hypoxia. In contrast, bicuculline increased Ve and Vt relative to DMSO during room air breathing and after 10-30 min of hypoxic exposure in obese rats, but it did not increase Ve at 5 min of hypoxemia. Bicuculline increased Vo(2 peak) relative to DMSO in obese Zucker rats. We conclude that endogenous GABA acting on GABA(A) receptors can modulate Ve and Vo(2 peak) in obese but not in lean Zucker rats, whereas endogenous GABA acting on GABA(B) receptors modulates f during hypoxia (5-20 min) in obese rats in a very different manner from that when acting on GABA(A) receptors.

Animals↗
PubMed1999

Bidirectional effects of the neuroactive steroid tetrahydrodeoxycorticosterone on GABA-activated Cl- currents in cultured rat hypothalamic neurons.

1. The non-genomic effects of tetrahydrodeoxycorticosterone (THDOC; 5-alpha-pregnane-3-alpha, 21-diol-20-one) were studied in cultured hypothalamic neurons of the rat. 2. The effects of THDOC (10 nM - 1 microM) on responses to different concentrations of exogenously applied GABA and on spontaneous inhibitory postsynaptic currents (IPSCs) were measured with whole-cell voltage clamp recordings. 3. Application of GABA induced inward currents with dose-dependently increasing amplitudes (up to 3.9 nA at a holding potential of -20 mV). High doses of THDOC (100 nM-1 microM) induced small inward currents on its own (14+/-3 and 24+/-3 pA, respectively). 4. Simultaneous application of 10 microM GABA with 100 nM or 1 microM THDOC increased current amplitudes by 125 and 128%, respectively. At 10 nM THDOC exerted no consistent effects on GABA currents. 5. Responses to 1 microM of GABA were modulated in a bidirectional manner by different doses of THDOC: 10 nM THDOC reduced the amplitude of GABA responses to 80% (P=0.018, n=15), whereas 100 nM and 1 microM THDOC enhanced the GABA response to 115 and 180% (P=0.0007, n = 15), respectively. 6. The time constant of decay of spontaneous inhibitory postsynaptic currents (IPSCs) was reversibly increased from 91+/-10 to 314+/-34 ms (n=3) by the application of THDOC (1 microM). The amplitudes of the IPSCs were not affected by THDOC. 7. These data indicate that THDOC modulates GABA responses of hypothalamic neurons in a bidirectional manner, resulting in a complex tuning of neuronal excitability in the hypothalamus.

Animals↗
PubMed1999

Benzodiazepines do not modulate desensitization of recombinant alpha1beta2gamma2 GABA(A) receptors.

Previous studies suggest that diazepam (DZP) increases the desensitization rate of GABA(A) receptors, although this effect could simply be a consequence of the DZP-induced increase in GABA sensitivity rather than a direct modulation of desensitization kinetics. To distinguish these two possibilities, voltage clamp recordings were performed on rat alpha1beta2gamma2 GABA(A) receptors expressed in Xenopus laevis oocytes. Complete GABA concentration-response relationships were obtained in the absence and presence of 1 microM DZP and the observed shift in GABA sensitivity (approximately 2.5-fold) was used to adjust GABA and GABA plus DZP to the same level of activation. In this case, DZP had no significant effect on either the rate of onset or recovery from desensitization. This suggests that the apparent effect of DZP on the rate of desensitization is secondary to the increase in GABA sensitivity and not due to a direct effect on the process of desensitization.

Animals↗
PubMed1992

Pharmacological discrimination of N-type from L-type calcium current and its selective modulation by transmitters.

GABA and norepinephrine inhibit high voltage-activated calcium current in chick sensory neurons. Using specific pharmacological tools, we have dissected this current into two components: the major one is omega-conotoxin sensitive and dihydropyridine resistant (N-type) while the minor one is dihydropyridine sensitively and omega-conotoxin resistant (L-type). The ability to selectively eliminate these two components has allowed us to determine whether the transmitters target the same or different channel types. Both GABA and norepinephrine modulate the N-type component as evidenced by their lack of effect on (1) omega-conotoxin-resistant current and (2) pure L-type tail current, prolonged by a dihydropyridine calcium channel agonist. This simple pharmacological profile will allow future tests of the significance of the two channel types in regulating sensory neuron functions.

Animals↗
PubMed2006

An interaction between benzodiazepines and neuroactive steroids at GABA A receptors in cultured hippocampal neurons.

Neurosteroids are modulators of several receptors and ion channels and are implicated in the pathophysiology of several neuropsychiatric diseases including hepatic encephalopathy (HE). The neurosteroid, allopregnanolone, a positive allosteric modulator of GABA(A) receptors, accumulates in the brains of HE patients where it can potentiate GABA(A) receptor-mediated responses. Attenuation of the effects of neurosteroids on GABA-ergic neurotransmission is therefore of interest for the management of HE. In the present study, we determined the effect of the benzodiazepine partial inverse agonist, Ro15-4513, and the benzodiazepine antagonist, flumazenil on modulation of the GABA(A) mediated chloride currents by allopregnanolone and on spontaneous synaptic activity in cultured hippocampal neurons using the patch-clamp technique. Allopregnanolone (0.03-0.3 microM), dose-dependently potentiated GABA-induced currents, an action significantly reduced by Ro15-4513 (10 microM). In contrast, flumazenil (10 microM) had no effect on the ability of allopregnanolone to potentiate GABA(A) currents but it blocked the effects of Ro15-4513. The frequency of spontaneous synaptic activity was significantly reduced in the presence of allopregnanolone (0.1 microM) from 1.5+/-0.7 to 0.1+/-0.04Hz. This action was partially reversed by Ro15-4513 (10 microM) but was not significantly influenced by flumazenil (10 microM). These findings suggest that the beneficial affects of Ro15-4513 in experimental HE result from attenuation of the effects of neurosteroids at GABA(A) receptors. Our results may provide a rational basis for the use of benzodiazepine inverse agonists in the management and treatment of hepatic encephalopathy in patients with liver failure.

Affinity Labels↗
PubMed2004

Gating allosterism at a single class of etomidate sites on alpha1beta2gamma2L GABA A receptors accounts for both direct activation and agonist modulation.

At clinical concentrations, the potent intravenous general anesthetic etomidate enhances gamma-aminobutyric acid, type A (GABA(A)) receptor activity elicited with low gamma-aminobutyric acid (GABA) concentrations, whereas much higher etomidate concentrations activate receptors in the absence of GABA. Therefore, GABA(A) receptors may possess two types of etomidate sites: high affinity GABA-modulating sites and low affinity channel-activating sites. However, GABA modulation and direct activation share stereoselectivity for the (R)(+)-etomidate isomer and display parallel dependence on GABA(A) beta subunit isoforms, suggesting that these two actions may be mediated by a single class of etomidate site(s) that exert one or more molecular effects. In this study, we assessed GABA modulation by etomidate using leftward shifts of electrophysiological GABA concentration responses in cells expressing human alpha1beta2gamma2L receptors. Etomidate at up to 100 microm reduced GABA EC(50) values by over 100-fold but without apparent saturation, indicating the absence of high affinity etomidate sites. In experiments using a partial agonist, P4S, etomidate both reduced EC(50) and increased maximal efficacy, demonstrating that etomidate shifts the GABA(A) receptor gating equilibrium toward open states. Results were quantitatively analyzed using equilibrium receptor gating models, wherein a postulated class of equivalent etomidate sites both directly activates receptors and enhances agonist gating. A Monod-Wyman-Changeux co-agonist mechanism with two equivalent etomidate sites that allosterically enhance GABA(A) receptor gating independently of agonist binding most simply accounts for direct activation and agonist modulation. This model also correctly predicts the actions of etomidate on GABA(A) receptors containing a point mutation that increases constitutive gating activity.

Allosteric Site↗
PubMedDate not supplied

[Neuroprotective and cerebrovascular effects of GABA mimetics].

The paper is devoted to the role of GABA system in the pharmacotherapy of ischemic brain injuries. In an analysis of the neuroprotector activity of GABA-mimetics, both their involvement in the maintenance of a balance between exciting and inhibiting processes and participation of the GABAergic mechanisms in regulation of the cerebrovascular tone are considered because proper blood supply is an important factor in the successful therapy of patients with ischemic brain injuries. Data available in the literature and the results of original investigations are summarized to assess the cerebrovascular and neuroprotector properties of GABA, as well as agonists and modulators of GABA receptors (muscimol, picamilon, phelbamate, clomethiazole, etc.). Particular attention is given to the neutroprotector and cerebrovascular activity of a new drug composition GABA-mimetic pirrolidone and pyroglutamic acid. This drug is capable of improving the cerebral blood supply, limiting the zone of ischemic injury, preventing an increase in the level of lactate and lipid peroxidation products, modifying nitric oxide content, and restoring the psychoneurological status of experimental animals with ischemic brain injury models.

Animals↗
PubMed2006

Efficacy and the discriminative stimulus effects of negative GABAA modulators, or inverse agonists, in diazepam-treated rhesus monkeys.

In benzodiazepine (BZ)-dependent animals, the effects of negative GABA(A) modulators at BZ sites are not clearly related to differences in negative efficacy (i.e., inverse agonist activity). A flumazenil discriminative stimulus in diazepam (5.6 mg/kg/day)-treated rhesus monkeys was used to test the hypothesis that the effects of negative GABA(A) modulators at BZ sites do not vary as a function of efficacy in BZ-dependent animals. Negative GABA(A) modulators varying in efficacy were studied in combination with positive modulators acting at different modulatory sites (BZ, barbiturate, and neuroactive steroid sites). The negative modulators Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-alpha]-[1,4]benzodiazepine-3-carboxylate) and ethyl beta-carboline-3-carboxylate (beta-CCE) substituted for the flumazenil discriminative stimulus. Acute pretreatment with diazepam (3.2 and 10 mg/kg s.c., in addition to 5.6 mg/kg/day p.o.), pentobarbital (3.2 and 10 mg/kg), or pregnanolone (1 and 3.2 mg/kg) attenuated the flumazenil discriminative stimulus and also attenuated the flumazenil-like discriminative stimulus effects of Ro 15-4513 and beta-CCE. Attenuation of the discriminative stimulus effects of flumazenil, Ro 15-4513, and beta-CCE did not systematically vary as a function of negative efficacy. Compared with their discriminative stimulus effects in untreated monkeys discriminating midazolam, both pregnanolone and pentobarbital were relatively more potent than diazepam in attenuating the discriminative stimulus effects of flumazenil, Ro 15-4513, and beta-CCE in diazepam-treated monkeys. These results show that the discriminative stimulus effects of BZ-site neutral and negative modulators are not different in BZ-dependent animals trained to discriminate flumazenil, and extend the results of a previous study showing that positive modulators acting at non-BZ sites are especially potent in attenuating the effects of flumazenil in diazepam-treated monkeys (i.e., diazepam withdrawal).

Animals↗
PubMed2000

Neurotransmitter-mediated control of neuronal firing in the red nucleus of the rat: reciprocal modulation between noradrenaline and GABA.

The electrical activity of neurons from the red nucleus, a mesencephalic structure involved in motor control, is under the influence of several neurotransmitters released from afferent fibers and/or from local interneurons. We have investigated the combined effects of gamma-aminobutyric acid (GABA) and noradrenaline (NA), both present at high levels in the red nucleus, on the firing activity of single rubral neurons recorded extracellularly in vivo on anesthetized adult rats. NA inhibited the firing activity of a large part of rubral neurons and induced excitatory or biphasic inhibitory/excitatory effects in a smaller group of cells. Neuronal firing was also inhibited by GABA in all the cells studied. When the effect of GABA was tested during continuous applications of NA, the magnitude of GABA response was modified in 58% of the cells: the effect of GABA was potentiated by NA in half of the responding neurons and was decreased in the remaining half. NA-induced potentiation of GABA response was mimicked by the alpha(2)-adrenoceptor agonist clonidine and was abolished by the alpha(2)-adrenoceptor antagonist yohimbine. On the other side, the decrease of GABA response was reproduced by the beta-adrenoceptor agonist isoprenaline and was blocked by timolol, an antagonist of beta-adrenoceptors. Neuronal firing activity was reduced by nipecotic acid, an inhibitor of GABA reuptake mechanism, and was instead increased during application of the GABA(A) receptor antagonist bicuculline, suggesting that rubral neurons in vivo were under tonic control by endogenous GABA. Both the inhibitory and the excitatory effects of NA were reduced in the presence of nipecotic acid and were instead potentiated during application of bicuculline, suggesting that NA responses were modified by endogenous GABA. Taken together, our results indicate a reciprocal modulation between the effects of GABA and NA on neuronal firing activity in the red nucleus of the rat: GABA depresses the responsiveness of rubral neurons to NA, whereas NA is able either to potentiate or to decrease the effects of GABA by activation of alpha(2)- and beta-adrenoceptors, respectively. The functional significance of such interaction, as well as the possible implication in diseases affecting motor control, will be discussed.

Action Potentials↗
PubMed1998

Benzodiazepine modulation of recombinant alpha1beta3gamma2 GABA(A) receptor function efficacy determination using the Cytosensor microphysiometer.

Gamma-aminobutyric acid (GABA) dose dependently increased extracellular acidification rate in Ltk cells stably expressing human recombinant alpha1beta3gamma2 GABA(A) receptors but had no effect in non-transfected controls. Cells seeded at 1 x 10(5) cells/cup, with 4-5 days induction, had basal acidification rates of 105+/-2 microVs(-1) at 37 degrees C (mean+/-standard error of mean, n=37). GABA responses had a characteristic time-course with an initial alkalinisation followed by a peak of acidification, which was optimized by increasing agonist exposure from 15 s to 25-30 s. The maximum concentration of GABA tested (100 microM) produced a 40+/-2% increase over basal acidification rate (n=3), with an EC50 of 15.5 microM and a Hill slope of 1.5. Responses were specifically antagonized by bicuculline and could be modulated by benzodiazepine ligands with varying efficacies. Full benzodiazepine agonists flunitrazepam (1 microM) and zolpidem (10 microM) significantly potentiated the response to 10 microM GABA by 124+/-15% (n=7) and 117+/-23% (n=3), respectively. The partial agonist bretazenil (100 nM) produced a 45+/-13% (n=3) potentiation whilst the inverse agonist DMCM (10 microM) (methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) inhibited the response to 20 microM GABA by 53+/-5%. The microphysiometer offers an alternative functional measure for GABA(A) receptors with the sensitivity to measure subtle modulatory effects of benzodiazepine site ligands and to determine their relative efficacy.

Animals↗
PubMed1980

Interaction of SQ 20009 and GABA-like drugs as modulators of benzodiazepine receptor binding.

SQ 20009, a new anxiolytic drug structurally unrelated to GABA or benzodiazepines, has two modulatory effects on the binding of 3H-flunitrazepam to membranes from rat cerebellum. Thus, SQ 20009 has a direct and chloride ion dependent stimulatory effect on benzodiazepine receptor binding which in turn appears to be modulated by the associated GABA receptor. In addition SQ 20009 has indirect effects on benzodiazepine receptor binding since it enhances the potency of GABA and muscimol to stimulate 3H-flunitrazepam binding.

Animals↗
PubMed2004

Differential GABAB Receptor Modulation of Ethanol Effects on GABA(A) synaptic activity in hippocampal CA1 neurons.

We tested the hypothesis that differential sensitivity to ethanol of synaptic GABA(A) somatic and dendritic inhibitory postsynaptic currents (IPSCs) in hippocampal CA1 pyramidal neurons could be due to differences in the extent of GABA(B) receptor activity at GABAergic synapses in these two hippocampal subfields. Our present results show that dendritic (distally evoked) GABA IPSCs contain a larger GABA(B) IPSC component of the total GABA IPSC than the somatic (proximally evoked) subfield. The inhibition of GABA(B) receptors by pretreatment of hippocampal slices with CGP-52432 [3[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxymethyl) phosphinic acid], a selective GABA(B) receptor antagonist, changes the basal ethanol-insensitive, distally evoked GABA(A) IPSCs to become more sensitive to ethanol. In addition, paired-pulse stimulation of the proximal and distal subfields of hippocampal pyramidal neurons shows that ethanol alone increases the probability of GABA release at proximal but not distal regions. Changes by ethanol on the probability of GABA release are only seen at distal locations during GABA(B) blockade. Finally, when the modulation of presynaptic GABA(B) receptors is minimized by the local application of 10 mM GABA directly onto somatic or dendritic GABAergic synaptic regions, postsynaptic GABA(B) receptors seem to exert significant negative (inhibiting) influence on the effects of ethanol on GABA(A) IPSCs in the distal subfields of CA1 pyramidal neurons. Together, our data suggest that differences in both presynaptic and postsynaptic GABA(B) receptor activity at these GABAergic synapses may modulate the differential ethanol sensitivity of proximal and distal GABA IPSCs(A) in hippocampal CA1 pyramidal neurons.

Animals↗