Potentiation of gamma-aminobutyric acid type A receptor-mediated synaptic currents by pentobarbital and diazepam in immature hippocampal CA1 neurons.
Previous studies have demonstrated age-dependent changes in the expression of gamma-aminobutyric acid type A (GABAA) benzodiazepine receptor binding sites and mRNAs encoding GABAA receptor subunits during postnatal development. However, little is known about the pharmacology of GABAA-mediated synaptic events in immature brain neurons. The effects of pentobarbital and diazepam were examined on the GABAA-mediated inhibitory postsynaptic current (IPSC) in postnatal 2- to 8-day-old (PN 2-8) and 18- to 30-day-old (PN 18-30) hippocampal CA1 neurons, using whole-cell recordings in brain slices. In both age groups of immature neurons recorded with an internal solution containing 2 mM ATP, application of diazepam at a concentration as low as 10 nM consistently potentiated the IPSC and Cl- currents evoked by local ejection of GABA (GABA currents). Pretreatment with the benzodiazepine antagonist, flumazenil, blocked the diazepam-induced potentiation of the IPSC, which suggested a direct action of diazepam on the GABAA/benzodiazepine receptor complex. With a patch pipette solution containing no added ATP, similar application of diazepam caused consistent potentiation of the IPSC in PN 18-30 neurons but not in PN 2-8 neurons. In contrast, pentobarbital potentiated the IPSCs with or without internally applied ATP in the neurons of both age groups. The authors suggest that functional GABAA/benzodiazepine receptors are expressed in neonatal CA1 hippocampal neurons. However, their sensitivity to benzodiazepines is altered by intracellular ATP.
Toronto Hospital Research Institute, Department of Physiology, University of Toronto, Ontario, Canada.
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Zhang
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Weiner
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PL
Carlen
D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D003975:Diazepam / Q000494:pharmacology*; D004357:Drug Synergism; D005442:Flumazenil / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D010424:Pentobarbital / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D000255:Adenosine Triphosphate; D010424:Pentobarbital; D003975:Diazepam