Strain Differences in Picrotoxin Seizure Threshold

Burt, George S.

doi:10.1038/193301a0

Cited by 11 publications

(3 citation statements)

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“…In parallel, increased GABA release with unaltered glutamatergic transmission in cerebral cortex (van Brederode et al, 2001) was associated with spontaneous seizures in Kv1.1-null mice (Brew et al, 2007;Rho et al, 1999;Smart et al, 1998). Although the Kv1 channels underlying altered GABAergic inhibition are potentially different, both findings are at odds with data showing seizure control following therapeutic enhancement of GABAergic transmission and seizurogenic properties of GABA A R blockade (Burt, 1962;Paul et al, 1979). Additionally, although the mechanisms by which NMDAR antagonists reduce major depressive symptoms remain unclear, our findings of reduced action potential-dependent GABA release are at odds with the popular, but controversial, GABA-deficit hypothesis of major depression (Croarkin et al, 2010;Hasler, 2010;Luscher et al, 2010).…”

Section: Potential Role Of Altered Gaba Transmission and Kv1 Channel mentioning

confidence: 79%

Increased Kv1 Channel Expression May Contribute to Decreased sIPSC Frequency Following Chronic Inhibition of NR2B-Containing NMDAR

Shao

Rittase

et al. 2012

Neuropsychopharmacol

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Numerous studies have documented the effects of chronic N-methyl-D-aspartate receptor (NMDAR) blockade on excitatory circuits, but the effects on inhibitory circuitry are not well studied. NR2A- and NR2B-containing NMDARs play differential roles in physiological processes, but the consequences of chronic NR2A- or NR2B-containing NMDAR inhibition on glutamatergic and GABAergic neurotransmission are unknown. We investigated altered GABAergic neurotransmission in dentate granule cells and interneurons following chronic treatment with the NR2B-selective antagonist, Ro25,6981, the NR2A-prefering antagonist, NVP-AAM077, or the non-subunit-selective NMDAR antagonist, D-APV, in organotypic hippocampal slice cultures. Electrophysiological recordings revealed large reductions in spontaneous inhibitory postsynaptic current (sIPSC) frequency in both granule cells and interneurons following chronic Ro25,6981 treatment, which was associated with minimally altered sIPSC amplitude, miniature inhibitory postsynaptic current (mIPSC) frequency, and mIPSC amplitude, suggesting diminished action potential-dependent GABA release. Chronic NVP-AAM077 or D-APV treatment had little effect on these measures. Reduced sIPSC frequency did not arise from downregulated GABA(A)R, altered excitatory or inhibitory drive to interneurons, altered interneuron membrane properties, increased failure rate, decreased action potential-dependent release probability, or mGluR/GABA(B) receptor modulation of GABA release. However, chronic Ro25,6981-mediated reductions in sIPSC frequency were occluded by the K+ channel blockers, dendrotoxin, margatoxin, and agitoxin, but not dendrotoxin-K or XE991. Immunohistochemistry also showed increased Kv1.2, Kv1.3, and Kv1.6 in the dentate molecular layer following chronic Ro25,6981 treatment. Our findings suggest that increased Kv1 channel expression/function contributed to diminished action potential-dependent GABA release following chronic NR2B-containing NMDAR inhibition and that these Kv1 channels may be heteromeric complexes containing Kv1.2, Kv1.3, and Kv1.6.

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Section: Potential Role Of Altered Gaba Transmission and Kv1 Channel mentioning

confidence: 79%

Increased Kv1 Channel Expression May Contribute to Decreased sIPSC Frequency Following Chronic Inhibition of NR2B-Containing NMDAR

Shao

Rittase

et al. 2012

Neuropsychopharmacol

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“…Binding of picrotoxin to β2/β3 subunits of the receptor effectively blocks the chloride channel, resulting in a post-synaptic neuron that is more easily excitable and prone to hyperexcitability. As such, picrotoxin-induced toxicity is epileptogenic [10,23-25]. There is compelling evidence that taurine interacts with the GABAergic system via the GABA A receptor [19,25-30].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological characterization of GABAA receptors in taurine-fed mice

2010

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BackgroundTaurine is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. Chronic supplementation of taurine in drinking water to mice increases brain excitability mainly through alterations in the inhibitory GABAergic system. These changes include elevated expression level of glutamic acid decarboxylase (GAD) and increased levels of GABA. Additionally we reported that GABAA receptors were down regulated with chronic administration of taurine. Here, we investigated pharmacologically the functional significance of decreased / or change in subunit composition of the GABAA receptors by determining the threshold for picrotoxin-induced seizures. Picrotoxin, an antagonist of GABAA receptors that blocks the channels while in the open state, binds within the pore of the channel between the β2 and β3 subunits. These are the same subunits to which GABA and presumably taurine binds.MethodsTwo-month-old male FVB/NJ mice were subcutaneously injected with picrotoxin (5 mg kg-1) and observed for a) latency until seizures began, b) duration of seizures, and c) frequency of seizures. For taurine treatment, mice were either fed taurine in drinking water (0.05%) or injected (43 mg/kg) 15 min prior to picrotoxin injection.ResultsWe found that taurine-fed mice are resistant to picrotoxin-induced seizures when compared to age-matched controls, as measured by increased latency to seizure, decreased occurrence of seizures and reduced mortality rate. In the picrotoxin-treated animals, latency and duration were significantly shorter than in taurine-treated animas. Injection of taurine 15 min before picrotoxin significantly delayed seizure onset, as did chronic administration of taurine in the diet. Further, taurine treatment significantly increased survival rates compared to the picrotoxin-treated mice.ConclusionsWe suggest that the elevated threshold for picrotoxin-induced seizures in taurine-fed mice is due to the reduced binding sites available for picrotoxin binding due to the reduced expression of the beta subunits of the GABAA receptor. The delayed effects of picrotoxin after acute taurine injection may indicate that the two molecules are competing for the same binding site on the GABAA receptor. Thus, taurine-fed mice have a functional alteration in the GABAergic system. These include: increased GAD expression, increased GABA levels, and changes in subunit composition of the GABAA receptors. Such a finding is relevant in conditions where agonists of GABAA receptors, such as anesthetics, are administered.

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“…Strain differences have been observed in the picrotoxin seizure threshold in mice (Burt 1962) and recent evidence has also revealed the existence of strain differences in benzodiazepine receptor binding in rats (Shephard et al 1982). A paper by File et al (1985) compared the anticonvulsant potency of a single dose of diazepam against pentylenetetrazol-induced seizures with in vivo receptor occupancy for four strains of mice.…”

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confidence: 97%

Evidence of strain differences in GABA-benzodiazepine coupling

Wilks

File

Martin³

1987

Psychopharmacology

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The effects of a single dose of oxazepam on seizure threshold, receptor occupancy and brain oxazepam concentration were investigated at several time points after drug treatment in two inbred strains of mice (NIH and C3H/HE). The C3H/HE strain showed a greater sensitivity to the effects of both pentylenetetrazol and oxazepam. Furthermore, the C3H/HE strain showed decreases in both receptor occupancy and seizure threshold across time, whereas the NIH strain showed no change in either measure. Although within-strain correlations were observed between seizure threshold and receptor occupancy, the C3H/HE strain had similar seizure thresholds to the NIH strain throughout but lower percentage receptor occupancies, thus a between-strain correlation was not observed. The C3H/HE strain had a higher number of specific benzodiazepine binding sits and these results may reflect a strain difference in GABA-benzodiazepine receptor coupling. In a further experiment, the development of acute tolerance to the effects of oxazepam was investigated. Brain concentrations of oxazepam and receptor occupancies were determined for each strain of mouse, at two different time points (1.5 and 7.5 h after drug treatment), at which equivalent seizure thresholds were obtained by manipulating the starting dose of oxazepam. For each strain, when equivalent seizure thresholds were observed at different time points, equivalent receptor occupancies were also observed. However, a trend towards higher brain concentrations of oxazepam at the later time point was detected for the two strains, suggesting that there may be some decrease across time in the affinity of the receptor for oxazepam.

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Strain Differences in Picrotoxin Seizure Threshold

Cited by 11 publications

References 4 publications

Increased Kv1 Channel Expression May Contribute to Decreased sIPSC Frequency Following Chronic Inhibition of NR2B-Containing NMDAR

Increased Kv1 Channel Expression May Contribute to Decreased sIPSC Frequency Following Chronic Inhibition of NR2B-Containing NMDAR

Pharmacological characterization of GABAA receptors in taurine-fed mice

Evidence of strain differences in GABA-benzodiazepine coupling

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