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.
Zhang
L
L
Toronto Hospital Research Institute, Department of Physiology, University of Toronto, Ontario, Canada.
Weiner
J L
JL
Carlen
P L
PL
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