Possible involvement of K(ATP) channels in the control of 5-HT neurons.
The possible involvement of ATP-sensitive potassium channels in the control of the electrical activity of central serotoninergic neurons was investigated by recording their firing rate in the dorsal raphe nucleus of rat brain stem slices exposed to various blockers and openers of these channels. Whereas the channel openers lemakalim and aprikalim produced no change in the firing rate of these neurons, the channel blockers glibenclamide and gliquidone were strongly inhibitory. As expected from an effect through ATP-sensitive potassium channels, the inhibition by glibenclamide could be prevented in a competitive manner by lemakalim and aprikalim. In contrast, the inactive isomer of the latter drug, RP 61499, did not alter the glibenclamide effect. In addition to the channel openers, the GABA receptor antagonists, bicuculline and phaclofen, but not the antagonist of somato-dendritic 5-HT1A autoreceptors, (-)tertatolol, prevented the negative influence of glibenclamide on the firing rate of serotoninergic neurons. This suggests that GABA acting at both GABAA and GABAB receptors (but not serotonin through the possible stimulation of autoreceptors) was responsible for the effect of glibenclamide. Accordingly, the blockade by the latter drug of ATP-sensitive potassium channels on GABAergic interneurons probably triggered the release of GABA, which in turn, inhibited serotoninergic neurons. In agreement with this hypothetical mechanism, autoradiographic studies demonstrated that ATP-sensitive potassium channels are not located on serotoninergic neurons (but probably on GABAergic interneurons) as the extensive lesion of these neurons by 5,7-dihydroxytryptamine did not reduce the specific labelling of the dorsal raphe nucleus by [3H]glibenclamide.
INSERM U288, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
S
S
Haj-Dahmane
A M
AM
Laporte
V
V
Vantalon
C M
CM
Fattaccini
M
M
Hamon
L
L
Lanfumey
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D004594:Electrophysiology; D058787:GABA-A Receptor Antagonists; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010847:Picolines / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D011714:Pyrans / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists; D013453:Sulfonylurea Compounds / Q000494:pharmacology
D001578:Benzopyrans; D058787:GABA-A Receptor Antagonists; D007004:Hypoglycemic Agents; D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; D011758:Pyrroles; D012702:Serotonin Antagonists; D013453:Sulfonylurea Compounds; D019806:Cromakalim; D012701:Serotonin; C061043:aprikalim; D000255:Adenosine Triphosphate; C010969:gliquidone; D005905:Glyburide