Inhibition of the 5-HT(1A) receptor-mediated inwardly rectifying K(+) current by dextromethorphan in rat dorsal raphe neurones.
The effect of dextromethorphan (DM) on the inwardly rectifying K(+) currents mediated by 5-HT(1A) receptors in acutely dissociated dorsal raphe (DR) neurones of rats was studied using nystatin-perforated patch and conventional whole-cell patch recording configurations under voltage-clamp conditions. DM rapidly and reversibly inhibited the K(+) currents induced by 10(-7) M 5-HT in a concentration-dependent manner with a half-maximum inhibitory concentration of 1.43 x 10(-5) M. The inhibitory effect of DM was neither voltage- nor use-dependent. DM caused a suppression of the maximum response of the 5-HT concentration-response curve, thus suggesting a non-competitive type of inhibition. In neurones perfused intracellularly with a pipette-solution containing the nonhydrolyzable GTP analog GTPgammaS, 5-HT activated K(+) currents in an irreversible manner. DM suppressed the current irreversibly activated by intracellular GTPgammaS even in the absence of the agonist. DM also inhibited the inwardly rectifying K(+) currents regulated by alpha(2)-adrenoceptors in freshly isolated rat locus coeruleus neurones. These results suggest that DM may inhibit the G-protein coupled inwardly rectifying K(+) channels, but not the neurotransmitter receptors, in the central nervous system.
Ishibashi
H
H
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, 862-0973, Kumamoto, Japan.
Kuwano
K
K
Takahama
K
K
D000818:Animals; D003915:Dextromethorphan / Q000494:pharmacology*; D004594:Electrophysiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009761:Nystatin / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D011903:Raphe Nuclei / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology*
D007476:Ionophores; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D018341:Receptors, Adrenergic, alpha-2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D009761:Nystatin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D003915:Dextromethorphan