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Klaus Albus - One of the best experts on this subject based on the ideXlab platform.
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Effects of γ-aminobutyric acid (GABA) Agonists and a GABA uptake inhibitor on pharmacoresistant seizure like events in organotypic hippocampal slice cultures
Epilepsy Research, 2009Co-Authors: Abdul Wahab, Uwe Heinemann, Klaus AlbusAbstract:Summary Purpose Seizure like events (SLEs) induced by low magnesium or 4-aminopyridine in organotypic hippocampal slice cultures (OHSCs) are resistant to standard antiepileptic drugs including phenobarbital, and 1,4-benzodiazepines [Albus, K., Wahab, A., Heinemann, U., 2008. Standard antiepileptic drugs fail to block epileptiform activity in rat organotypic hippocampal slice cultures. Br. J. Pharmacol. 154, 709–724]. The present study was undertaken in order to test the effects of other compounds on SLEs in OHSCs that enhance GABA-mediated actions. Methods Six to 12 days old Wistar rats were used to cultivate OHSCs according to the interface method [Stoppini, L., Buchs, P.A., Muller, D., 1991. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 37, 173–182]. Neuronal activity and extracellular potassium concentration were recorded under submerged conditions. SLEs were induced by lowering the magnesium concentration. The effects of GABA A Agonists muscimol and isoguvacine, the GABA B agonist baclofen, the GABA uptake blocker nipecotic acid and the neurosteroid alfaxalone on induction and ongoing SLEs were analyzed. Results Low magnesium induced SLEs were dose dependently suppressed by the GABA A receptor Agonists muscimol, isoguvacine and alfaxalone and by the GABA uptake inhibitor nipecotic acid whereas the GABA B receptor agonist baclofen attenuated but did not suppress SLE. Discussion Our findings demonstrate that in OHSCs GABA has an inhibitory effect on SLEs. Proconvulsant effects of GABA Agonists on spontaneous neuronal activity and seizure like activity were never observed. Our findings exclude a possible contribution of impaired/altered GABA-ergic mechanisms based on immaturity of receptors and/or low receptor density to seizure susceptibility and pharmacoresistance in OHSCs.
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Effects of gamma-aminobutyric acid (GABA) Agonists and a GABA uptake inhibitor on pharmacoresistant seizure like events in organotypic hippocampal slice cultures.
Epilepsy research, 2009Co-Authors: Abdul Wahab, Uwe Heinemann, Klaus AlbusAbstract:Seizure like events (SLEs) induced by low magnesium or 4-aminopyridine in organotypic hippocampal slice cultures (OHSCs) are resistant to standard antiepileptic drugs including phenobarbital, and 1,4-benzodiazepines [Albus, K., Wahab, A., Heinemann, U., 2008. Standard antiepileptic drugs fail to block epileptiform activity in rat organotypic hippocampal slice cultures. Br. J. Pharmacol. 154, 709-724]. The present study was undertaken in order to test the effects of other compounds on SLEs in OHSCs that enhance GABA-mediated actions. Six to 12 days old Wistar rats were used to cultivate OHSCs according to the interface method [Stoppini, L., Buchs, P.A., Muller, D., 1991. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 37, 173-182]. Neuronal activity and extracellular potassium concentration were recorded under submerged conditions. SLEs were induced by lowering the magnesium concentration. The effects of GABA(A) Agonists muscimol and isoguvacine, the GABA(B) agonist baclofen, the GABA uptake blocker nipecotic acid and the neurosteroid alfaxalone on induction and ongoing SLEs were analyzed. Low magnesium induced SLEs were dose dependently suppressed by the GABA(A) receptor Agonists muscimol, isoguvacine and alfaxalone and by the GABA uptake inhibitor nipecotic acid whereas the GABA(B) receptor agonist baclofen attenuated but did not suppress SLE. Our findings demonstrate that in OHSCs GABA has an inhibitory effect on SLEs. Proconvulsant effects of GABA Agonists on spontaneous neuronal activity and seizure like activity were never observed. Our findings exclude a possible contribution of impaired/altered GABA-ergic mechanisms based on immaturity of receptors and/or low receptor density to seizure susceptibility and pharmacoresistance in OHSCs.
Robert L. Balster - One of the best experts on this subject based on the ideXlab platform.
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Discriminative stimulus effects of presynaptic GABA Agonists in pentobarbital-trained rats.
Pharmacology Biochemistry and Behavior, 2002Co-Authors: Doreen M. Grech, Robert L. BalsterAbstract:Abstract The discriminative stimulus effects of indirect-acting GABAergic drugs were compared to those of pentobarbital (PB) and midazolam in rats trained to discriminate 5 mg/kg PB from saline under a two-lever fixed-ratio 32 schedule of food reinforcement. PB and midazolam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Valproic acid, an antiepileptic drug and GABA transaminase inhibitor, substituted for PB but not only at a dose that produced response rate suppression. ViGABAtrin, an irreversible GABA transaminase inhibitor, failed to substitute for PB, but did produce a dose-dependent decrease in response rates. The GABA uptake inhibitors, 1-[2-[bis[4-(trifluoromethyl)phenyl]- methoxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (CI-966) and (R(−)-N-[4,4-bis(3-methylthien-2-yl) but-3-enyl] nipecotic acid HCl (tiagabine), produced no greater than 40% PB-lever responding. Aminoxyacetic acid (AOAA), which is described as a nonselective presynaptic GABA agonist, yielded a maximum of 43% PB-lever responding. These results indicate that the discriminative stimulus effects of the indirect GABAA Agonists, PB and midazolam, although similar to one another, differ from those of presynaptic GABAergic drugs. Differences in the discriminative stimulus properties of GABA transaminase inhibitors and uptake inhibitors also exist, indicating that not all presynaptic GABA Agonists have similar behavioral profiles. These results contribute to a further understanding of the similarities and differences in the behavioral effects of drugs that enhance GABAergic neurotransmission.
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Muscimol-Like Discriminative Stimulus Effects of GABA Agonists in Rats
Pharmacology Biochemistry and Behavior, 1998Co-Authors: Hendree E Jones, Robert L. BalsterAbstract:Abstract The discriminative stimulus effects of GABAergic drugs were evaluated in rats trained to discriminate the direct GABAA agonist, muscimol (1.0 mg/kg IP), from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. Another direct GABAA agonist, THIP, produced full substitution for muscimol, however, at doses producing response rate decreasing effects. Diazepam, an allosteric modulator of GABA-mediated postsynaptic inhibition, yielded a maximum of 50% muscimol-lever responding at a dose that also decreased rates of responding. Partial substitution for muscimol (maximal levels of 71% muscimol-lever responding) was also produced by the GABA agonist progabide. Propofol, an anesthetic that potentiates GABAA receptor function, and the GABA uptake inhibitor, tiagabine, produced no greater than 53 and 48% muscimol-lever responding, respectively. Valproic acid, a reversible GABA transaminase inhibitor, failed to substitute for muscimol, and viGABAtrin, an irreversible GABA transaminase inhibitor, yielded a maximal 46% muscimol-lever responding. These results demonstrate the pharmacological specificity of muscimol discrimination by showing that only direct Agonists for the GABA site on the GABAA receptor complex produce full substitution. GABA Agonists acting by other mechanisms can be distinguished from muscimol and THIP in this procedure.
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Pentobarbital-like discriminative stimulus effects of direct GABA Agonists in rats
Psychopharmacology, 1993Co-Authors: Doreen M. Grech, Robert L. BalsterAbstract:The discriminative stimulus effects of direct and indirect-acting GABAergic drugs were investigated in rats trained to discriminate 5 mg/kg pentobarbital (PB) from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. PB and diazepam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Muscimol, thiomuscimol and 4,5,6,7-tetrahydroisoxazolo [5,4-c]-pyridin-3-ol (THIP) produced intermediate levels of pentobarbital-lever responding (40–60%), accompanied by dose-dependent decreases in rates of responding following THIP and muscimol administration. The GABA_A agonist progabide and its metabolite 4-{[(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]amino}] butyric acid (SL 75102) also partially substituted for PB, producing means of 39–73% PB-lever responding. The GABA_B agonist, baclofen, completely failed to substitute for PB even at doses that decreased rates of responding. These results show that the discriminative stimulus effects of indirect GABA_A Agonists, PB and diazepam, although similar to one another, differ from those of direct GABA_A receptor Agonists, which produced only partial substitution for PB. The GABA_B agonist, baclofen, can be distinguished by lacking any ability to substitute for PB. These results contribute to a further understanding of the similarities and differences in the behavioral effects of different types of GABA Agonists.
Einar Stefánsson - One of the best experts on this subject based on the ideXlab platform.
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GABA Agonists fail to protect the retina from ischemia reperfusion injury
Experimental Eye Research, 2009Co-Authors: Sindri Traustason, Thor Eysteinsson, Bjarni A. Agnarsson, Einar StefánssonAbstract:Abstract The purpose of this study was to test the hypothesis that ischemia/reperfusion injury in the rat retina may be ameliorated by reducing retinal metabolism with either hypothermia or inhibitory GABA Agonists. The intraocular pressure of each right eye in rats was raised to 130 mmHg for 60 min with the left eye serving as normal control. The rats were divided into four groups in terms of drug and hypothermia treatment: (1) Untreated ischemia, (2) Hypothermia, (3) Baclofen/midazolam and (4) Baclofen/muscimol. Electroretinogram was recorded before ischemia and again after 10-day reperfusion. Histological analysis with H&E staining and cell counts was performed. Untreated ischemia/reperfusion resulted in severely reduced ERG responses. The ERG b-wave was reduced from 423 ± 144 μV to 130 ± 91 μV (mean ± SD, n = 5). With hypothermia the ERG b-wave was reduced from 499 ± 80 μV to 237 ± 111 μV ( n = 4). With combinations of baclofen and midazolam the ERG b-wave was reduced from 432 ± 96 μV to 104 ± 67 μV ( n = 7). In baclofen/muscimol treated eyes the ERG b-wave went from 426 ± 101 μV to 148 ± 118 μV ( n = 6). The histological tissue damage was severe in untreated ischemia and the baclofen/midazolam and baclofen/muscimol groups, but less severe in the hypothermia group. The GABA Agonists do not provide any protection in our ischemia/reperfusion model. Our results are consistent with earlier reports that hypothermia may be helpful in ischemic conditions in the retina.
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GABA Agonists fail to protect the retina from ischemia-reperfusion injury.
Experimental Eye Research, 2008Co-Authors: Sindri Traustason, Thor Eysteinsson, Bjarni A. Agnarsson, Einar StefánssonAbstract:Abstract The purpose of this study was to test the hypothesis that ischemia/reperfusion injury in the rat retina may be ameliorated by reducing retinal metabolism with either hypothermia or inhibitory GABA Agonists. The intraocular pressure of each right eye in rats was raised to 130 mmHg for 60 min with the left eye serving as normal control. The rats were divided into four groups in terms of drug and hypothermia treatment: (1) Untreated ischemia, (2) Hypothermia, (3) Baclofen/midazolam and (4) Baclofen/muscimol. Electroretinogram was recorded before ischemia and again after 10-day reperfusion. Histological analysis with H&E staining and cell counts was performed. Untreated ischemia/reperfusion resulted in severely reduced ERG responses. The ERG b-wave was reduced from 423 ± 144 μV to 130 ± 91 μV (mean ± SD, n = 5). With hypothermia the ERG b-wave was reduced from 499 ± 80 μV to 237 ± 111 μV ( n = 4). With combinations of baclofen and midazolam the ERG b-wave was reduced from 432 ± 96 μV to 104 ± 67 μV ( n = 7). In baclofen/muscimol treated eyes the ERG b-wave went from 426 ± 101 μV to 148 ± 118 μV ( n = 6). The histological tissue damage was severe in untreated ischemia and the baclofen/midazolam and baclofen/muscimol groups, but less severe in the hypothermia group. The GABA Agonists do not provide any protection in our ischemia/reperfusion model. Our results are consistent with earlier reports that hypothermia may be helpful in ischemic conditions in the retina.
Abdul Wahab - One of the best experts on this subject based on the ideXlab platform.
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Effects of γ-aminobutyric acid (GABA) Agonists and a GABA uptake inhibitor on pharmacoresistant seizure like events in organotypic hippocampal slice cultures
Epilepsy Research, 2009Co-Authors: Abdul Wahab, Uwe Heinemann, Klaus AlbusAbstract:Summary Purpose Seizure like events (SLEs) induced by low magnesium or 4-aminopyridine in organotypic hippocampal slice cultures (OHSCs) are resistant to standard antiepileptic drugs including phenobarbital, and 1,4-benzodiazepines [Albus, K., Wahab, A., Heinemann, U., 2008. Standard antiepileptic drugs fail to block epileptiform activity in rat organotypic hippocampal slice cultures. Br. J. Pharmacol. 154, 709–724]. The present study was undertaken in order to test the effects of other compounds on SLEs in OHSCs that enhance GABA-mediated actions. Methods Six to 12 days old Wistar rats were used to cultivate OHSCs according to the interface method [Stoppini, L., Buchs, P.A., Muller, D., 1991. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 37, 173–182]. Neuronal activity and extracellular potassium concentration were recorded under submerged conditions. SLEs were induced by lowering the magnesium concentration. The effects of GABA A Agonists muscimol and isoguvacine, the GABA B agonist baclofen, the GABA uptake blocker nipecotic acid and the neurosteroid alfaxalone on induction and ongoing SLEs were analyzed. Results Low magnesium induced SLEs were dose dependently suppressed by the GABA A receptor Agonists muscimol, isoguvacine and alfaxalone and by the GABA uptake inhibitor nipecotic acid whereas the GABA B receptor agonist baclofen attenuated but did not suppress SLE. Discussion Our findings demonstrate that in OHSCs GABA has an inhibitory effect on SLEs. Proconvulsant effects of GABA Agonists on spontaneous neuronal activity and seizure like activity were never observed. Our findings exclude a possible contribution of impaired/altered GABA-ergic mechanisms based on immaturity of receptors and/or low receptor density to seizure susceptibility and pharmacoresistance in OHSCs.
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Effects of gamma-aminobutyric acid (GABA) Agonists and a GABA uptake inhibitor on pharmacoresistant seizure like events in organotypic hippocampal slice cultures.
Epilepsy research, 2009Co-Authors: Abdul Wahab, Uwe Heinemann, Klaus AlbusAbstract:Seizure like events (SLEs) induced by low magnesium or 4-aminopyridine in organotypic hippocampal slice cultures (OHSCs) are resistant to standard antiepileptic drugs including phenobarbital, and 1,4-benzodiazepines [Albus, K., Wahab, A., Heinemann, U., 2008. Standard antiepileptic drugs fail to block epileptiform activity in rat organotypic hippocampal slice cultures. Br. J. Pharmacol. 154, 709-724]. The present study was undertaken in order to test the effects of other compounds on SLEs in OHSCs that enhance GABA-mediated actions. Six to 12 days old Wistar rats were used to cultivate OHSCs according to the interface method [Stoppini, L., Buchs, P.A., Muller, D., 1991. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 37, 173-182]. Neuronal activity and extracellular potassium concentration were recorded under submerged conditions. SLEs were induced by lowering the magnesium concentration. The effects of GABA(A) Agonists muscimol and isoguvacine, the GABA(B) agonist baclofen, the GABA uptake blocker nipecotic acid and the neurosteroid alfaxalone on induction and ongoing SLEs were analyzed. Low magnesium induced SLEs were dose dependently suppressed by the GABA(A) receptor Agonists muscimol, isoguvacine and alfaxalone and by the GABA uptake inhibitor nipecotic acid whereas the GABA(B) receptor agonist baclofen attenuated but did not suppress SLE. Our findings demonstrate that in OHSCs GABA has an inhibitory effect on SLEs. Proconvulsant effects of GABA Agonists on spontaneous neuronal activity and seizure like activity were never observed. Our findings exclude a possible contribution of impaired/altered GABA-ergic mechanisms based on immaturity of receptors and/or low receptor density to seizure susceptibility and pharmacoresistance in OHSCs.
Akitane Mori - One of the best experts on this subject based on the ideXlab platform.
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Monoamine release in the rat striatum is induced by 8-guanidinovaleric acid and inhibited by GABA Agonists
Life Sciences, 1995Co-Authors: Hideaki Kabuto, Isao Yokoi, Kazuo Iwaya, Akitane MoriAbstract:Abstract δ-Guanidinovaleric acid (GVA) is an endogenous convulsant and is thought to be a specific γ-aminobutyric acid (GABA) antagonist. In this study, we examined the effects of GVA and GABA Agonists, GABA, muscimol and baclofen, on the release of dopamine (DA) and serotonin (5-HT) in the rat striatum using a brain dialysis technique. GVA produced a significant increase in the amount of DA and 5-HT released compared with controls. Both GABA (10mM) and muscimol (10mM) inhibited the GVA-induced release of DA and 5-HT. Muscimol was a more potent inhibitor of 5-HT release than DA release. Baclofen (10mM) inhibited only the GVA-induced DA release. These results suggest that the activation of GABA receptors inhibits the release of DA and 5-HT in the striatum, and that the dopaminergic system regulates GABA-B receptors and the serotonergic system mainly regulates GABA-A receptors.
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Monoamine release in the rat striatum is induced by 8-guanidinovaleric acid and inhibited by GABA Agonists
Life sciences, 1995Co-Authors: Hideaki Kabuto, Isao Yokoi, Kazuo Iwaya, Akitane MoriAbstract:delta-Guanidinovaleric acid (GVA) is an endogenous convulsant and is thought to be a specific gamma-aminobutyric acid (GABA) antagonist. In this study, we examined the effects of GVA and GABA Agonists, GABA, muscimol and baclofen, on the release of dopamine (DA) and serotonin (5-HT) in the rat striatum using a brain dialysis technique. GVA produced a significant increase in the amount of DA and 5-HT released compared with controls. Both GABA (10mM) and muscimol (10mM) inhibited the GVA-induced release of DA and 5-HT. Muscimol was a more potent inhibitor of 5-HT release than DA release. Baclofen (10mM) inhibited only the GVA-induced DA release. These results suggest that the activation of GABA receptors inhibits the release of DA and 5-HT in the striatum, and that the dopaminergic system regulates GABA-B receptors and the serotonergic system mainly regulates GABA-A receptors.