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M Gordey

Publications and source records attributed to M Gordey.

4 recordsLinked to original sources
PubMed2001

Altered effects of ethanol in NR2A(DeltaC/DeltaC) mice expressing C-terminally truncated NR2A subunit of NMDA receptor.

Phosphorylation of C-termini of receptor subunits is thought to play a significant role in modulation of N-methyl-D-aspartic acid (NMDA) receptor function. To investigate whether the C-terminus of the NR2A subunit is involved in determining the sensitivity of NMDA receptors to ethanol we compared the effects of ethanol in vitro on NMDA-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 and dentate gyrus (DG) of adult male NR2A(DeltaC/DeltaC) mice lacking the C-terminus of NR2A subunit and in their parental strain C57Bl/6. We also tested the in vivo effects of a hypnotic dose of ethanol in C57Bl/6 and NR2A(DeltaC/DeltaC) mice and their F2 offspring. Ifenprodil (10 microM) was used to distinguish between the NR2A and NR2B components of NMDA fEPSPs. Ethanol (100 mM) in the presence of ifenprodil inhibited the CA1 NR2A-mediated component of NMDA fEPSPs two times more in NR2A(DeltaC/DeltaC) than in C57Bl/6. Ethanol inhibition of the CA1 NR2B-mediated component was five to seven times lower in NR2A(DeltaC/DeltaC) than in C57Bl/6. In the DG ethanol had similar effects in the two strains. In vivo administration of ethanol (4 g/kg) induced sedation of similar duration in both strains of mice. A second administration of ethanol 7 days after the initial injection revealed an increased ethanol sensitivity of NR2A(DeltaC/DeltaC) and F2(DeltaC/DeltaC) mice including a shortened time to loss of righting reflex and an increased sleep time. The sensitization of NR2A(DeltaC/DeltaC) mice to alcohol was not accompanied by an altered ethanol sensitivity of NMDA fEPSPs recorded in vitro. Our data are consistent with the inhibitory action of ethanol on NMDA receptors being mediated by a site other than the intracellular C-terminus of the NR2A subunit. The altered sensitivities to ethanol of both NR2A- and NR2B-mediated responses in the CA1 of NR2A(DeltaC/DeltaC) imply that NR2A- and NR2B subunit-containing NMDA receptors may be linked by a common target of ethanol.

Animals↗
PubMed2000

Differential sensitivity of recombinant GABA(A) receptors expressed in Xenopus oocytes to modulation by topiramate.

PURPOSE: This study evaluated the modulatory effects of topiramate (TPM) on various subtypes of recombinant rat gamma-aminobutyric acid A (GABA(A)) receptors expressed in Xenopus oocytes. METHODS: Specific subunits of GABA(A) receptors were expressed in Xenopus oocytes. Voltage-clamp recordings of currents were performed after application of TPM (1-100 microM) to these oocytes in the presence or absence of GABA. RESULTS: In a concentration-dependent fashion, TPM (1-100 microM) reversibly inhibited GABA-evoked Cl- currents in oocytes expressing either alpha1beta2gamma2S and alpha2beta2gamma2S recombinant GABA(A) receptors and reduced the current-fading rate in alpha1beta2gamma2S-expressing oocytes. Topiramate was effective at GABA concentrations of 1-10 microM but not at 100 microM. Topiramate (1-100 microM) potentiated GABA-evoked Cl- currents and increased the fading rate in oocytes expressing the alpha6beta2gamma2S GABA(A) receptor. It had no effect on Cl- currents mediated through the alpha4beta2gamma2S receptor or through the mixed population of GABA(A) receptors expressed from rat brain mRNA. In general, the observed effects of TPM were more pronounced on fading rates than on peak Cl- currents. CONCLUSIONS: These results indicate that TPM may affect desensitization of GABA(A) receptors as assessed by changes in the fading rates of GABA-evoked Cl- currents, possibly by effects on second-messenger systems.

Animals↗
PubMed1995

Zinc modulation of GABAA receptor-mediated chloride flux in rat hippocampal slices.

We studied the effect of ZnCl2 application on GABAA receptor-mediated 36CI- flux in microsacs prepared from whole rat hippocampus and in region-specific hippocampal slices. Slices were obtained from the dentate gyrus (DG), which contains the zinc-enriched hilar region, and from the CA1 region which contains lower levels of endogenous zinc. Muscimol (10 microM)-evoked 36Cl- flux was significantly reduced by ZnCl2 (100 microM) in hippocampal microsacs. In hippocampal slices, muscimol (50 microM)-evoked 36Cl- efflux was higher in CA1 (112.5 +/- 27.9% above basal efflux rate) than in DG slices (29.7 +/- 5.6%). In the presence of ZnCl2, the muscimol effect on efflux rate in CA1 and DG regions was decreased to 10.6 +/- 5.4% and 6.9 +/- 4.9%, respectively. Preincubation with the zinc chelator, tetrakis(2-pyridylmethyl)ethylenediamine (TPEN, 20 microM), caused a significant increase in muscimol-evoked 36Cl- efflux only in DG slices (57.2 +/- 7.0%), suggesting that GABAA receptors in the DG of rat hippocampus under physiological conditions may function under the inhibitory influence of endogenous chelatable zinc. In intracellular recordings, ZnCl2 (100 microM) application had no effect on the responses to GABA applied perisomatically or in the dendritic region of CA1 neurons. The lack of Zn2+ effect on the postsynaptic GABAA receptor-mediated responses suggests that the decreases of the 36Cl- efflux observed in the biochemical assays may be due to zinc action on neurons other than the principal pyramidal CA1 cells, and possibly the non-neuronal cell populations.

Animals↗