The K+ channel opener diazoxide enhances glutamatergic currents and reduces GABAergic currents in hippocampal neurons.
1. The effect of diazoxide, an opener of ATP-sensitive K+ channels (KATP channels) has been investigated in the rat hippocampal slices by the use of extracellular and intracellular recording techniques. 2. In control solution, diazoxide enhanced the CA1 and CA3 field excitatory postsynaptic potentials (EPSPs) and produced interictal activities in CA3. These effects were neither prevented by KATP blockers, including glibenclamide (3-30 microM) or tolbutamide (500 microM), nor mimicked by another KATP opener such as galanine (1 microM); thus these effects are probably not mediated by KATP channels. 3. Using intracellular recording, we then studied, in CA3 pyramidal neurons, the effect of diazoxide on the EPSPs and the fast and slow inhibitory postsynaptic potentials (IPSPs). 4. In presence of bicuculline (10 microM) and phaclofen (50 microM), to block, respectively, fast and slow IPSPs, diazoxide reversibly enhanced the EPSPs. 5. In presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM), to block EPSPs, diazoxide reversibly decreased both fast and slow IPSPs. 6. These effects of diazoxide on the EPSPs and fast and slow IPSPs were associated neither with a change of the reversal potential of the EPSPs or the fast and slow IPSPs nor with a change of the input resistance and membrane potential. 7. Using single electrode voltage-clamp technique, we then tested the effects of diazoxide on the currents generated by applications of glutamate or gamma-aminobutyric acid (GABA) -A and -B analogues. 8. In presence of tetrodotoxin (TTX; 1 microM), diazoxide reversibly enhanced the peak currents evoked by alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate (AMPA; 3-5 microM), quisqualate (5-10 microM) and N-methyl-D-aspartate (NMDA; 10 microM), but not those evoked by kainate (1-3 microM). 9. In presence of TTX (1 microM), diazoxide reversibly decreased the GABA- (1-5 mM), isoguvacine- (30-60 microM), and baclofen- (10-30 microM) mediated peak currents. 10. It is concluded that, in the hippocampus, diazoxide enhances the excitatory glutamatergic currents and reduces the GABAergic inhibition, thus generating paroxystic activities. We suggest that these effects are mediated by second messenger cascades.
Crépel
V
V
Institut National de la Santé et de la Recherche Médicale U29, Paris, France.
Rovira
C
C
Ben-Ari
Y
Y
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003981:Diazoxide / Q000494:pharmacology*; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects; D005971:Glutamates / Q000378:metabolism* / Q000494:pharmacology; D018698:Glutamic Acid; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D005971:Glutamates; D007473:Ion Channels; D015221:Potassium Channels; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000255:Adenosine Triphosphate; D003981:Diazoxide