Diminished allopregnanolone enhancement of GABA(A) receptor currents in a rat model of chronic temporal lobe epilepsy.
1. Neurosteroid modulation of GABA(A) receptors present on dentate granule cells (DGCs) acutely isolated from epileptic (epileptic DGCs) or control rats (control DGCs) was studied by application of GABA with or without the modulators and by measuring the amplitude of peak whole-cell currents. 2. In epileptic DGCs, GABA efficacy (1394 +/- 277 pA) was greater than in control DGCs (765 +/- 38 pA). 3. Allopregnanolone enhanced GABA-evoked currents less potently in epileptic DGCs (EC50 = 92.7 +/- 13.4 nM) than in control DGCs (EC50 = 12.9 +/- 2.3 nM). 4. Pregnenolone sulfate inhibited GABA-evoked currents with similar potency and efficacy in control and epileptic DGCs. 5. Diazepam enhanced GABA-evoked currents less potently in epileptic (EC50 = 69 +/- 14 nM) compared to the control DGCs (EC50 = 29.9 +/- 5.7 nM). 6. There were two different patterns of zolpidem modulation of GABA(A) receptor currents in the epileptic DGCs. In one group, zolpidem enhanced GABA(A) receptor currents but with reduced potency compared to the control DGCs (EC50 = 134 +/- 20 nM vs. EC50 = 52 +/- 13 nM). In the second group of epileptic DGCs zolpidem inhibited GABA(A) receptor currents, an effect not observed in control DGCs. 7. Epileptic DGCs were more sensitive to Zn2+ inhibition of GABA(A) receptor currents (IC50 = 19 +/- 6 microM) compared to control (IC50 = 94.7 +/- 7.9 microM). 8. This study demonstrates significant differences between epileptic and control DGCs. We conclude that (1) diminished sensitivity of GABA(A) receptors of epileptic DGCs to allopregnanolone can increase susceptibility to seizures; (2) reduced sensitivity to diazepam and zolpidem, and increased sensitivity to Zn2+ indicate that loss of allopregnanolone sensitivity is likely to be due to altered subunit expression of postsynaptic GABA(A) receptors present on epileptic DGCs; and (3) an inverse effect of zolpidem in some epileptic DGCs demonstrates the heterogeneity of GABA(A) receptors present on epileptic DGCs.
Mtchedlishvili
Z
Z
Department of Neurology, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
Bertram
E H
EH
Kapur
J
J
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002908:Chronic Disease; D003975:Diazepam / Q000494:pharmacology; D004553:Electric Conductivity; D004833:Epilepsy, Temporal Lobe / Q000503:physiopathology*; D018755:GABA Agonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D011280:Pregnanolone / Q000494:pharmacology*; D011284:Pregnenolone / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology*; D015032:Zinc / Q000494:pharmacology; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000927:Anticonvulsants; D018755:GABA Agonists; D058787:GABA-A Receptor Antagonists; D011725:Pyridines; D011963:Receptors, GABA-A; C018370:pregnenolone sulfate; D005680:gamma-Aminobutyric Acid; D011284:Pregnenolone; D000077334:Zolpidem; D011280:Pregnanolone; D015032:Zinc; D003975:Diazepam