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At least 595 records · Page 33Linked to original sources
PubMed2005

Enhancement of the synchronized firing of CA1 pyramidal cells by medial septum preconditioning: time-dependent involvement of muscarinic cholinoceptors and GABAB receptors.

Activation of the medial septum (MS) enhances the synchronized firing of pyramidal cells in the hippocampus. At least two distinct mechanisms might be recruited in this process: GABAergic inhibition of hippocampal inhibitory interneurons and cholinergic enhancement of pyramidal cell excitability. In the present study, a field potential recording in urethane anaesthetised rats was used to show that MS preconditioning with brief high-frequency burst stimulation markedly enhanced Schaffer collateral/commissural (SC/C) synaptically evoked population spikes in the CA1 area without significant alteration in the initial slope of SC/C field excitatory postsynaptic potentials (fEPSPs). An early phase (< approximately 125 ms) of the facilitation of neuronal discharge was inhibited by intracerebroventricular (i.c.v.) injection of the GABA(B) receptor antagonist CGP 52432 (200 nmol/5 microl). In contrast, the muscarinic cholinoceptor antagonist scopolamine (20 nmol/5 microl) inhibited a later phase ( approximately 150-300 ms) of the population spike facilitation. These findings support an important role for both cholinergic and GABAergic mediated septal drive in the tuning of signal conversion within the hippocampus as well as in securing the cortical feedback from the hippocampus.

Animals↗
PubMed2005

A parametric assessment of GABA antagonist effects on paired-pulse facilitation in the rat anterior cingulate cortex.

Paired-pulse facilitation (PPF) is a form of short-term plasticity that can be used qualitatively to characterize the synaptic effects of neuroactive compounds. As we have shown previously, CNQX has a marked effect on PPF which can be measured quantitatively. The aim of the present study was to examine quantitatively possible differences in the effects of the post- and pre-synaptic GABA antagonists on PPF in vitro. Experiments were performed on slices taken from the coronal anterior cingulate cortex (ACC) of Sprague-Dawley rats. The stimuli consisted of a pair of biphasic pulses with an inter-pulse interval of 40ms. Evoked extracellular field potentials in layers 2/3 of the ACC were recorded. Quantitative assessment of PPF was achieved by calculating two parameters, the PPFmax (theoretical maximal PPF) and the Stmax (stimulus intensity that produces the PPFmax). Picrotoxin treatment produced increases in both the PPFmax and Stmax, by increasing the stimulus producing the half-maximal effect. In contrast, CGP-55845 treatment produced an increase in only the PPFmax, which was due to an alteration in the asymptotic values of the response amplitudes. Our findings show that the effect of different GABA receptor antagonists on short-term synaptic facilitation in the ACC may be assessed and specified quantitatively.

Animals↗
PubMed2006

The synaptic mechanism of direction selectivity in distal processes of starburst amacrine cells.

Patch-clamp recordings revealed that distal processes of starburst amacrine cells (SACs) received largely excitatory synaptic input from the receptive field center and nearly purely inhibitory inputs from the surround during both stationary and moving light stimulations. The direct surround inhibition was mediated mainly by reciprocal GABA(A) synapses between opposing SACs, which provided leading and prolonged inhibition during centripetal stimulus motion. Simultaneous Ca(2+) imaging and current-clamp recording during apparent-motion stimulation further demonstrated the contributions of both centrifugal excitation and GABA(A/C)-receptor-mediated centripetal inhibition to the direction-selective Ca(2+) responses in SAC distal processes. Thus, by placing GABA release sites in electrotonically semi-isolated distal processes and endowing these sites with reciprocal GABA(A) synapses, SACs use a radial-symmetric center-surround receptive field structure to build a polar-asymmetric circuitry. This circuitry may integrate at least three levels of interactions--center excitation, surround inhibition, and reciprocal inhibitions that amplify the center--surround antagonism-to generate robust direction selectivity in the distal processes.

Action Potentials↗
PubMed2004

Lamina-specific differences in GABA(B) autoreceptor-mediated regulation of spontaneous GABA release in rat entorhinal cortex.

Spontaneous synaptic inhibition plays an important role in regulating the excitability of cortical networks. Here we have investigated the role of GABA(B) autoreceptors in regulating spontaneous GABA release in the entorhinal cortex (EC), a region associated with temporal lobe epilepsies. We have previously shown that the level of spontaneous inhibition in superficial layers of the EC is much greater than that seen in deeper layers. In the present study, using intracellular and whole cell patch clamp recordings in rat EC slices, we have demonstrated that evoked GABA responses are controlled by feedback inhibition via GABA(B) autoreceptors. Furthermore, recordings of spontaneous, activity-independent inhibitory postsynaptic currents in layer II and layer V neurones showed that the GABA(B) receptor agonist, baclofen, reduced the frequency of GABA-mediated currents indicating the presence of presynaptic GABA(B) receptors in both layers. Application of the antagonist, CGP55845, blocked the effects of baclofen and also increased the frequency of GABA-mediated events above baseline, but the latter effect was restricted to layer V. This demonstrates that GABA(B) autoreceptors are tonically activated by synaptically released GABA in layer V, and this may partly explain the lower level of spontaneous GABA release in the deep layer.

Action Potentials↗
PubMed2005

Opposing roles for GABAA and GABAC receptors in short-term memory formation in young chicks.

The inhibitory neurotransmitter GABA has both inhibitory and enhancing effects on short-term memory for a bead discrimination task in the young chick. Low doses of GABA (1-3 pmol/hemisphere) injected into the multimodal association area of the chick forebrain, inhibit strongly reinforced memory, whereas higher doses (30-100 pmol/hemisphere) enhance weakly reinforced memory. The effect of both high and low doses of GABA is clearly on short-term memory in terms of both the time of injection and in the time that the memory loss occurs. We argue on the basis of relative sensitivities to GABA and to selective GABA receptor antagonists that low doses of GABA act at GABAC receptors (EC50 approximately 1 microM) and the higher doses of GABA act via GABAA receptors (EC50 approximately 10 microM). The selective GABAA receptor antagonist bicuculline inhibited strongly reinforced memory in a dose and time dependent manner, whereas the selective GABAC receptor antagonists TPMPA and P4MPA enhanced weakly reinforced in a dose and time dependent manner. Confirmation that different levels of GABA affect different receptor subtypes was demonstrated by the shift in the GABA dose-response curves to the selective antagonists. It is clear that GABA is involved in the control of short-term memory formation and its action, enhancing or inhibiting, depends on the level of GABA released at the time of learning.

Animals↗
PubMed2006

Concentration-dependent effects of anticonvulsant enaminone methyl 4-(4'-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate on neuronal excitability in vitro.

Enaminones are a novel group of compounds some of which possess anticonvulsant activity in in vivo animal models of seizures. We recently reported that some enaminones, including methyl 4-(4'-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate, depress glutamate-mediated excitatory synaptic transmission and that this may contribute to their anticonvulsant activity [Kombian SB, Edafiogho IO, Ananthalakshmi KVV (2005) Anticonvulsant enaminones depress excitatory synaptic transmission in the rat brain by enhancing extracellular GABA levels. Br J Pharmacol 145:945-953]. Here we studied the effects of methyl 4-(4'-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate, on the excitability of male rat (Sprague-Dawley) nucleus accumbens and hippocampal cells in vitro using whole-cell patch clamp recording techniques. At low, therapeutically relevant concentrations (0.3-10 microM), methyl 4-(4'-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate reversibly suppressed action potential firing rate in a concentration-dependent manner. This action potential suppression was present when GABA(A), GABA(B) and glutamate receptors were blocked with their antagonists. Furthermore, methyl 4-(4'-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate suppressed tetrodotoxin-sensitive sodium currents in these cells. At concentrations >/=100 microM, it induced inward currents and increased action potential firing frequency. The inward currents were without changes in input resistance and did not reverse polarity between -120 and -40 mV. These currents were independent of extracellular potassium, but were absent when extracellular sodium was replaced by choline and finally, were occluded by pretreatment with ouabain (200 microM). We conclude that methyl 4-(4'-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate directly inhibits action potential firing at therapeutically relevant concentrations by suppressing tetrodotoxin-sensitive sodium currents, while inducing an ouabain-sensitive current at high concentrations to excite neurons. These two actions of methyl 4-(4'-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate on neuronal excitability would have therapeutic implications in future clinical use of enaminones as anticonvulsants in seizure disorders.

Action Potentials↗
PubMed2004

Selective removal of gallium (III) from aqueous solutions containing zinc or aluminum using sodium di-(n-octyl) phosphinate.

Gallium was removed selectively from aqueous solutions containing zinc or aluminum using sodium di-(n-octyl) phosphinate as a ligand (NaL). At low pH or low mole ratios, the gallium was removed by complexation with the ligand as GaL(3(S)), while the zinc or the aluminum remained in the solution. Nearly complete separation of gallium was obtained. By increasing the amount of ligand or by increasing the pH, the zinc or aluminum remaining in the solution was then removed as a solid complex: ZnL(2(S)) or AlL(3(S)), respectively. At a pH between 1.5 and 2 and a mole ratio ligand to total metals of 0.75 for zinc solutions and 1.0 for aluminum solutions, more than 98% of the gallium was selectively removed with a high molar selectivity, alpha(Ga/Zn) and alpha(Ga/Al), respectively. Over 95% of gallium was recovered from the solid GaL(3(S)) complex by treatment of the complex with a 3M NaOH solution and diethyl ether. The gallium was concentrated in the aqueous solution to 4 times its initial concentration and the ligand was extracted into the ether phase. After evaporation of the ether, 95% of the ligand was regenerated in its sodium form as a solid.

Aluminum↗
PubMed2001

Potency and selectivity of RXP407 on human, rat, and mouse angiotensin-converting enzyme.

By screening phosphinic peptide libraries, we recently reported the discovery of RXP407 (Ac-Asp-PheY(PO2-CH2)LAla-Ala-NH2), a potent N-domain-selective inhibitor of recombinant human angiotensin-converting enzyme (ACE). Preliminary studies to evaluate the in vivo activity of RXP407 in rat led us to suspect possible differences in the binding property of RXP407 between human and rat ACE. The aim of the present study was thus to determine the potency of RXP407 toward rat and mouse ACEs, as compared to non-recombinant human ACE, and to assess the efficacy of this inhibitor in discriminating between the N- and C-domains of these ACE enzymes. By comparing the ability of RXP407 to block purified somatic and germinal ACE from mice, RXP407 was shown to be a potent N-domain-selective inhibitor of mouse somatic ACE, a behavior similar to that observed with human somatic ACE. In contrast, RXP407 appeared less potent toward purified ACE from rat and furthermore was unable to block ACE activity present in crude rat plasma. This study demonstrated that for further evaluation of the in vivo efficacy of RXP407, mice rather than rats should be used as the animal model. Thus, following the change in the Ac-S-D-K-P plasmatic levels, after i.v. injection of RXP407 to mice, will permit the potency and selectivity of this novel ACE inhibitor to be assessed.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Microscopic kinetics and energetics distinguish GABA(A) receptor agonists from antagonists.

Although agonists and competitive antagonists presumably occupy overlapping binding sites on ligand-gated channels, these interactions cannot be identical because agonists cause channel opening whereas antagonists do not. One explanation is that only agonist binding performs enough work on the receptor to cause the conformational changes that lead to gating. This idea is supported by agonist binding rates at GABA(A) and nicotinic acetylcholine receptors that are slower than expected for a diffusion-limited process, suggesting that agonist binding involves an energy-requiring event. This hypothesis predicts that competitive antagonist binding should require less activation energy than agonist binding. To test this idea, we developed a novel deconvolution-based method to compare binding and unbinding kinetics of GABA(A) receptor agonists and antagonists in outside-out patches from rat hippocampal neurons. Agonist and antagonist unbinding rates were steeply correlated with affinity. Unlike the agonists, three of the four antagonists tested had binding rates that were fast, independent of affinity, and could be accounted for by diffusion- and dehydration-limited processes. In contrast, agonist binding involved additional energy-requiring steps, consistent with the idea that channel gating is initiated by agonist-triggered movements within the ligand binding site. Antagonist binding does not appear to produce such movements, and may in fact prevent them.

Animals↗
PubMed1992

Microviscosity of human erythrocytes studied using hypophosphite two-spin order relaxation.

A new 31P NMR method is used to probe the cytoplasmic viscosity of human erythrocytes. The method is based on observing two-spin order relaxation of the 31P atom of the hypophosphite ion. This method is superior to our previous method, using the longitudinal relaxation time of the ion, because random field effects such as intermolecular dipole-dipole relaxation can be separated from intramolecular relaxation. This allows a more accurate determination of the effective reorientational correlation time from the measured intramolecular relaxation because it is now unaffected by random field effects. The new method also provides a means by which to estimate the random field effects. Both two-spin order and proton-decoupled T1 measurements were conducted on hypophosphite in water solutions at various temperatures, glycerol solutions of various viscosities, and in erythrocyte samples of various cell volumes. The results show that the effective reorientational correlation time of the hypophosphite ion varies from 7.2 to 15.2 ps in the cytoplasm of cells ranging in volume from 102 to 56 fl cells.

Cytoplasm↗
PubMed2000

New alpha-selective thermal glycosylation of acetyl-protected 2-acetamido-2-deoxy-beta-D-glucopyranosyl diphenylphosphinate.

This paper describes new alpha-selective thermal glycosylation using acetyl-protected 2-acetamido-2-deoxy-beta-D-glucopyranosyl diphenylphosphinate (4) as a glycosyl donor. When the glycosylation of 4 with 1-hexanol was carried out under various conditions, the conditions using trimethylsilyl trifluoromethanesulfonate as a promoter in nitromethane at reflux temperature were most suitable for the formation of the alpha anomer. The glycosylation of 4 with the other common alcohols gave corresponding alpha-glycosides in relatively high yields under the conditions. When cholesterol, a very steric hindered alcohol, was used as a glycosyl acceptor, alpha-glycoside was also produced predominantly.

Acetylation↗
PubMed2002

Recombinant GABA(B) receptors formed from GABA(B1) and GABA(B2) subunits selectively inhibit N-type Ca(2+) channels in NG108-15 cells.

Efficient transfection of NG108-15 cells with GABA(B) receptor subunits was achieved using polyethylenimine. Baclofen modulated high voltage-activated Ca(2+) current in differentiated cells transfected with GABA(B1) and GABA(B2) receptor subunits or with the GABA(B2) subunit alone, but not with the GABA(B1) subunit alone. Characteristics of the current modulation were very similar for cells transfected with GABA(B1/2) and GABA(B2) subunits. Using antisense oligonucleotides against GABA(B1) subunits and also western immunoblotting, we are able to show that NG108-15 cells contain endogenous GABA(B1) subunits. Therefore, functional receptors can be formed by the combination of native GABA(B1) subunits with transfected GABA(B2) subunits, in agreement with the proposed heteromeric structure of GABA(B) receptors. Finally, we used selective channel blockers to identify the subtypes of Ca(2+) channels that are modulated by GABA(B) receptors. In fact, in differentiated NG108-15 cells, the recombinant GABA(B) receptors couple only to N-type Ca(2+) channels.

Animals↗
PubMed1997

Opposite effects of GABAB receptor antagonists on absences and convulsive seizures.

In Wistar rats with spontaneous non-convulsive absence epilepsy, absence seizures were dose dependently suppressed by intraperitoneal administration of the GABAB receptor antagonists CGP 36742, 50-400 mg/kg, and CGP 56999, 0.25-0.75 mg/kg, and by bilateral microinjections of the same compounds into the lateral nuclei of the thalamus. In rats susceptible to audiogenic seizures, intraperitoneal administration of both GABAB receptor antagonists, at doses which suppressed absence seizures, facilitated the elicitation of sound-induced tonic seizures. In non-epileptic control rats, intraperitoneal injections of higher doses of CGP 36742 (800-2400 mg/kg) and CGP 56999 (3-6 mg/kg) induced delayed clonic convulsions, which were suppressed by pretreatment with baclofen. c-Fos protein was expressed after GABAB receptor antagonist-induced seizures in the cortex, hippocampus, amygdala, perirhinal and piriform cortex. Intra-cortical and hippocampal microinfusion of both GABAB receptor antagonists produced focal seizures. In conclusion, GABAB receptor antagonists suppress non-convulsive absence seizures by blocking thalamic GABAB receptors, while they induce convulsions in cortical and limbic structures.

Animals↗
PubMed2001

Developmental regulation of GABA(B) receptor function in rat spinal cord.

GABA(B) receptors are heterodimers coupled to G-proteins. The present study was undertaken to investigate activation of GABA(B) receptors in cerebral cortex and spinal cord using [35S]GTPgammaS binding assays, a direct measure of G-protein activity. The results revealed that the GABA(B) agonist baclofen stimulates GTPgammaS binding in cerebral cortex, with an ED50 of 50microM. This response is blocked by the GABA(B) receptor antagonist CGP 55845A (100nM). In contrast, baclofen-stimulated GTPgammaS binding was not observed in adult spinal cord tissue under similar incubation conditions, or after varying magnesium, calcium, GDP, [35S]GTPgammaS, or membrane concentrations in the assay medium. Stimulation of adult rat spinal cord muscarinic receptors did result in a concentration-related increase in [35S]GTPgammaS binding. Baclofen-stimulated GTPgammaS binding in adult spinal cord did not appear after peripheral inflammation, despite significant increases in GABA(B) subunit mRNA levels. As opposed to adult, appreciable GTPgammaS binding was observed in membranes prepared from spinal cords of rats within the first 14 days of postnatal development, suggesting that GABA(B) receptor function in the rat spinal cord is developmentally regulated. The results indicate that GABA(B) receptors may not be coupled to G-proteins in the adult rat spinal cord, or couple in a way that differs from that in newborns or adult cerebral cortex.

Age Factors↗
PubMed1998

Regulation of neurokinin-1 receptor expression by GABA(B) receptor agonists.

Activation of GABA(B) receptors produces analgesia in acute and chronic pain models. Data indicate that a possible mechanism for this effect is a GABA(B) receptor-induced blockade of neurokinin-1 (NK-1) receptor gene expression in the spinal cord. While much more potent GABA(B) receptor agonists (CGP 44532) have been developed, there is no information on their antinociceptive properties or their ability to influence NK-1 receptors. To address these issues, rats were treated with baclofen or CGP 44532 and tested for sedation, ataxia, and pain-related behaviors in a chronic pain model (formalin hindpaw injection). In a separate group of experiments the analgesic response to a single dose of CGP 44532 was tested prior, and subsequent to, its chronic administration. The results indicate that CGP 44532 is a substantially more potent analgesic than baclofen. In addition, after chronic administration baclofen was no longer capable of inducing analgesia or of inhibiting the increased expression of NK-1R mRNA and CGP 44532 was still fully effective in both regards. The results suggest that GABA(B) agonists could be clinically useful analgesics.

Animals↗
PubMed2001

Both GABA(B) receptor agonist and antagonists decreased brain stimulation reward in the rat.

The present experiments were designed to determine the role of GABA(B) receptor function on brain stimulation reward. Using a discrete-trial current-intensity threshold procedure, dose-effect functions were generated for the GABA(B) receptor agonist CGP 44532 (0-1.0 mg/kg, s.c.) and the GABA(B) receptor antagonists CGP 56433A (0-10.0 mg/kg, s.c.) and CGP 51176 (0-300.0 mg/kg, s.c.) on brain reward thresholds in rats. The GABA(B) receptor antagonists CGP 56433A and CGP 51176 were used also to examine interaction effects with the GABA(B) receptor agonist CGP 44532 on reward thresholds. Administration of the highest doses of both the GABA(B) receptor agonist and antagonists elevated reward thresholds. Thus, both the agonist and antagonists used induced a reward decrement when administered separately. In addition, the co-administration of either of the two receptor antagonists with the agonist induced an additive effect on thresholds, rather than blocking the agonist-induced threshold elevations. These results suggest that activation of GABA(B) receptors modulates intracranial self-stimulation behavior in a complex fashion, possibly through differential effects of GABA(B) agonists and antagonists on pre- and post-synaptic GABA(B) receptors.

Animals↗
PubMed2002

Spontaneous epileptiform activity mediated by GABA(A) receptors and gap junctions in the rat hippocampal slice following long-term exposure to GABA(B) antagonists.

Recent evidence suggests that excessive GABA(A) receptor-mediated transmission can lead to neuronal hyperexcitability and hypersynchrony. We show now that exposure of a rat hippocampal slice to GABA(B) receptor antagonists (CGP 55845A and CGP 35348) in the absence of ionotropic glutamatergic transmission leads to a progressive synchronization of spontaneous interneuronal activity. In about 30% of over 200 slices examined, the GABA(A)-mediated spontaneous activity produced field responses in the CA1 soma region with a positive-going phase of up to 5 mV, followed by a long-lasting negative deflection with a simultaneous extracellular K(+) transient. These bicarbonate-dependent GABAergic ictal-like events (GIEs) were associated with biphasic (hyperpolarizing/depolarizing) intracellular responses and with synchronous bursting of the pyramidal neurons. The GIEs could not be reversed by wash-out of the GABA(B) receptor antagonists or by baclofen, but they were inhibited by agonists acting on presynaptic mu-opioid and cannabinoid (CB1) receptors pointing to a down-regulation of presynaptic GABA(B) receptors. GIEs were dependent on intracellular carbonic anhydrase, and potentiated by maneuvers that increase intracellular pH. They were blocked by the Cx36-specific gap-junction (gj) blocker, quinine/quinidine, as well as by the broad-spectrum gj blocker, octanol. These data suggest that enhanced GABAergic activity with functional interneuronal connectivity via gjs is sufficient to trigger epileptiform activity in the absence of ionotropic glutamatergic transmission.

2-Amino-5-phosphonovalerate↗
PubMed2000

Impaired inhibition of epileptiform activity by baclofen, but not by adenosine in the weaver hippocampus.

The weaver defect results in a loss of baclofen- and adenosine-gated K+ conductance in the hippocampus of adult homozygous (wv/wv) mice. In addition, suppression of hippocampal epileptiform activity by baclofen is impaired (Jarolimek, W., Bäurle, J., Misgeld, U., 1998. Pore mutation in a G protein-gated inwardly rectifying K+ channel subunit causes loss of K+ dependent inhibition in weaver hippocampus. Journal of Neuroscience 18, 4001-4007). We used wv/wv and wild-type (+/+) mice to determine whether K+ conductance increases are essential for the suppression of epileptiform activity by R-baclofen and adenosine in disinhibited hippocampal slices. In wv/wv mice R-baclofen was less potent by two orders of magnitude in reducing the frequency of spontaneous synchronous burst discharges than in +/+ mice. Endogenous adenosine and adenosine A1 receptor agonists differed only slightly in their efficacy to inhibit spontaneous synchronous burst discharges in wv/wv and +/+ mice. The findings on adenosine A1 receptors suggest that the varied efficacy of R-baclofen in wv/wv and +/+ mice may not be explained solely on the basis of a loss of ligand-gated K+ conductance. Therefore, we investigated the affinity of GABA(B) receptors for the antagonist CGP55845A in wv/wv and +/+ hippocampi. Schild plot analysis revealed a K(D) for the GABA(B) antagonist CGP55845A 10 fold higher in wv/wv than in +/+ mice. The data suggest that an alteration of GABA(B) receptors could contribute to the reduced efficacy of R-baclofen to suppress hippocampal epileptiform activity in weaver mice, while the suppression by adenosine remains largely unaffected.

4-Aminopyridine↗