The distribution of antidiabetic sulfonylurea [( 3H]glibenclamide) binding sites is heterogeneous in rat brain. Pyramidal and extrapyramidal motor system contain the highest densities of sites, particularly in the substantia nigra and in the globus pallidus. Only low levels are present in the hypothalamic nuclei and the main medulla oblongata regions. In hippocampal formation the stratum lucidum and the stratum lacunosum moleculare of CA3 show an important density of glibenclamide binding sites. Electrophysiological studies with hippocampal slices show that glibenclamide blocks hyperpolarization induced by anoxia, suggesting the involvement of adenosine triphosphate-sensitive K+ channel in this early hyperpolarization event.

Intracellular recordings from rat hippocampal neurons in vitro during the first postnatal week revealed the presence of spontaneous giant depolarizing potentials (GDPs). These were generated by the synchronous discharge of a population of neurons. GDPs reversed polarity at -27 and -51 mV when recorded with KCl or K-methylsulphate filled electrodes, respectively. GDPs were blocked by the GABAA receptor antagonist bicuculline (10 microM). Iontophoretic or bath applications of GABA (10-300 microM) in the presence of tetrodotoxin (1 microM), induced a membrane depolarization or in voltage clamp experiments an inward current which reversed polarity at the same potential as GDPs. The response to GABA was blocked in a non-competitive manner by bicuculline (10 microM) and did not desensitize. GABA mediated GDPs were presynaptically modulated by N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Their frequency was reduced or blocked by NMDA receptor antagonists and by the rather specific non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The frequency of GDPs was enhanced by glycine and D-serine (10-30 microM) in a strychnine insensitive manner. This effect was blocked by AP-5, suggesting that it was mediated by the allosteric modulatory site of the NMDA receptor. These observations suggest that most of the 'excitatory' drive in immature neurons is mediated by GABA acting on GABAA receptors; furthermore excitatory amino acids modulate the release of GABA by a presynaptic action on GABAergic interneurons.

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